Effects of pca and dmae on the nematode caenorhabditis briggsae

Concentration of 6.8 mM DMAE did not retard age pigment accumulation in Caenorhabditis briggsae. However, when the nematodes were exposed to 6.8 mM PCA + 68 mM DMAE combined, the accumulation of age pigment was significantly retarded. A combination of 3.4 mM DMAE + 3.4 mM PCA had no effect on age pigment. It is concluded from this study that PCA and DMAE act in concert to produce the observed effect on age pigment. In respect to this parameter neither molecule was effective alone. The results indicate that the effect of centrophenoxine on age pigment might be enhanced by retarding the hydrolysis of centrophenoxine. The accumulation of electron dense aggregates, thought to be aggregates of cross-linked molecules, was reduced by 6.8 PCA + 6.8 DMAE. It is suggested that centrophenoxine be tested for its ability to remove random, unwanted cross-linkages in higher animals.     

Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation

Although it has been hypothesized that some of the somatic mutations found in tumors may occur before tumor initiation, there is little experimental or conceptual data on this topic. To gain insights into this fundamental issue, we formulated a mathematical model for the evolution of somatic mutations in which all relevant phases of a tissue’s history are considered. The model makes the prediction, validated by our empirical findings, that the number of somatic mutations in tumors of self-renewing tissues is positively correlated with the age of the patient at diagnosis. Importantly, our analysis indicates that half or more of the somatic mutations in certain tumors of self-renewing tissues occur before the onset of neoplasia. The model also provides a unique way to estimate the in vivo tissue-specific somatic mutation rates in normal tissues directly from the sequencing data of tumors. Our results have substantial implications for the interpretation of the large number of genome-wide cancer studies now being undertaken.     

Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization

Many current experimental results show the necessity of new conceptual approaches to understand hematopoietic stem cell organization. Recently, we proposed a novel theoretical concept and a corresponding quantitative model based on microenvironment-dependent stem cell plasticity. The objective of our present work is to subject this model to an experimental test for the situation of chimeric hematopoiesis. Investigating clonal competition processes in DBA/2-C57BL/6 mouse chimeras, we observed biphasic chimerism development with initially increasing but long-term declining DBA/2 contribution. These experimental results were used to select the parameters of the mathematical model. To validate the model beyond this specific situation, we fixed the obtained parameter configuration to simulate further experimental settings comprising variations of transplanted DBA/2-C57BL/6 proportions, secondary transplantations, and perturbation of stabilized chimeras by cytokine and cytotoxic treatment. We show that the proposed model is able to consistently describe the situation of chimeric hematopoiesis. Our results strongly support the view that the relative growth advantage of strain-specific stem cells is not a fixed cellular property but is sensitively dependent on the actual state of the entire system. We conclude that hematopoietic stem cell organization should be understood as a flexible, self-organized rather than a fixed, preprogrammed process.     

Salvage esophagectomy for recurrent tumors after definitive chemotherapy and radiotherapy.

OBJECTIVES: Some patients and oncologists choose to treat localized esophageal cancer with definitive chemotherapy and radiation therapy rather than surgery. A subset of these patients have local relapse without distant metastases and therefore have no other curative intent treatment option but salvage esophagectomy. METHODS: We reviewed our experience with salvage esophagectomy from 1987 to 2000 at M.D. Anderson Cancer Center (n = 13, salvage after chemotherapy and radiotherapy group) and compared the data with those of patients receiving esophagectomy in a planned fashion 4 to 6 weeks after preoperative chemotherapy and radiation therapy (n = 99, preoperative chemotherapy and radiotherapy group). RESULTS: Increases in morbidity were seen after resection in the salvage after chemotherapy and radiotherapy group relative to the preoperative chemotherapy and radiotherapy group: mechanical ventilation (9.0 days vs 3.3 days, P =.08), intensive care unit stay (11.2 days vs 5.1 days, P =.07), hospital stay (29.4 days vs 18.4 days, P =.03), and anastomotic leak rates (5/13 [39%] vs 7/99 [7%], P =.005). Operative mortality (within 30 days) also tended to be increased statistically nonsignificantly (2/13 [15%] vs 6/99 [6%], P =.2). Salvage esophagectomy resulted in long-term survival (25% 5-year survival) in a subset of patients. Improved survival after salvage esophagectomy was associated with early pathologic stage (T1 N0, T2 N0), prolonged time to relapse, and R0 surgical resection. CONCLUSION: Patients who undergo salvage esophagectomy for relapse of tumor after definitive chemoradiation therapy have increased morbidity, mortality, and hospital use relative to patients undergoing planned esophagectomy after preoperative chemoradiation. Nevertheless, long-term survival can be achieved in this group, and such treatment should be considered for carefully selected patients at an experienced center.     

Finite element analysis performed on radius and tibia HR‐pQCT images and fragility fractures at all sites in men

Few studies have investigated bone microarchitecture and biomechanical properties in men. This study assessed in vivo both aspects in a population of 185 men (aged 71 ± 10 years) with prevalent fragility fractures, compared to 185 controls matched for age, height, and weight, from the Structure of the Aging Men's Bones (STRAMBO) cohort. In this case‐control study, areal BMD (aBMD) was measured by DXA, bone microarchitecture was assessed by high resolution (HR)‐pQCT, and finite element (µFE) analysis was based on HR‐pQCT images of distal radius and tibia. A principal component (PC) analysis (PCA) was used to study the association of synthetic PCs with fracture by computing their odds ratio (OR [95%CI]) per SD change. Specific associations with vertebral fracture (n = 100), and nonvertebral fracture (n = 85) were also computed. At both sites, areal and volumetric BMD, cortical thickness and trabecular number, separation, and distribution were significantly worse in cases than in controls, with differences ranging from ?6% to 15%. µFE‐derived stiffness and failure load were 8% to 9% lower in fractures (p < .01). No difference in load distribution was found between the two groups. After adjustment for aBMD, only differences of µFE‐derived stresses, stiffness, and failure load at the tibia remained significant (p < .05). PCA resulted in defining 4 independent PCs, explaining 83% of the total variability of bone characteristics. Nonvertebral fractures were associated with PC1, reflecting bone quantity and strength at the radius (tibia) with OR = 1.64 [1.27–2.12] (2.21 [1.60–3.04]), and with PC2, defined by trabecular microarchitecture, with OR = 1.27 [1.00–1.61]. Severe vertebral fractures were associated with PC1, with OR = 1.56 [1.16–2.09] (2.21 [1.59–3.07]), and with PC2, with OR = 1.55 [1.17–2.06] (1.45 [1.06–1.98]). In conclusion, microarchitecture and biomechanical properties derived from µFE were associated with all types of fractures in men, showing that radius and tibia mechanical properties were relatively representative of distant bone site properties. © 2011 American Society for Bone and Mineral Research.     

Significance of acellular mucin pools in rectal carcinoma after neoadjuvant chemoradiotherapy

The presence of mucin pools lacking neoplastic epithelium ("acellular" mucin) in resection specimens of rectal carcinoma after neoadjuvant chemoradiotherapy (CRT) is a well-recognized phenomenon. The current recommendation by the College of American Pathologists is to regard acellular mucin as a type of treatment response and not as residual tumor. However, data-based evidence for or against such an approach is incomplete. In this study, we systematically analyzed the pattern and significance of mucin pools in 108 consecutive, prospectively collected resection specimens from patients who had uT3-4 and/or uN1 rectal cancer and were treated with preoperative long-course CRT. The 108 patients, 39 female and 69 male, had a median age of 58.5 years. With every tumor entirely examined in whole-mount sections, mucin pools were identified in 33 cases (33 of 108, 31%); in 16 (15%) they were all acellular. The mucin pools were focal (10% to 50% of the entire lesion) in 25 cases and extensive (>50%) in 8 cases. Mucin pools were also noted in the lymph nodes in 6 cases (6%); 3 of these were entirely acellular. Five cases had mucin pools in both the primary site and the lymph nodes. When acellular mucin was considered as "no residual tumor," the complete pathologic response rate for the entire cohort was 22% (24 of 108). The pathologic stage of the residual tumor (ypT) was 0 or 1 for 27 cases (25%) and 2 to 4 for 81 cases. The pathologic stage of nodal disease (ypN) was 0 for 83 (77%) and 1 or 2 for 25 cases. When acellular mucin was considered as "residual tumor," the complete pathologic response rate dropped to 17%; ypT was upstaged in 10 tumors and ypN was upstaged in 2 tumors. With a median follow-up of 31 months, the 3-year recurrence-free survival (RFS) was 73% for the entire group. Advanced pathologic response and low pathologic stage of the residual tumor (determined based on the depth of only viable tumor cells) correlated significantly with better RFS. However, the correlation between pathologic response and RFS became insignificant when acellular mucin pools were considered as residual tumor. Neither the presence of mucin pools nor their extent or cellularity had an impact on RFS. Furthermore, none of the 12 patients whose ypT or ypN was upstaged by acellular mucin had recurrent disease (3-y RFS of 100%). Thus, our results suggest that mucin pools in rectal carcinoma after neoadjuvant CRT do not have a significant impact on patient outcome, supporting the College of American Pathologists recommendation that only viable tumor cells, not acellular mucin, are to be interpreted as residual disease in the tumor pathologic staging.     

Classifications In Brief: American Spinal Injury Association (ASIA) Impairment Scale

Clinical Orthopaedics and Related Research® -     

A retrospective clinical study of 188 consecutive patients to examine the effectiveness of a biologically active cryopreserved human skin allograft (TheraSkin®) on the treatment of diabetic foot ulcers and venous leg ulcers

A biologically active human skin allograft, currently distributed under the brand name TheraSkin(?), was examined for safety and efficacy in the treatment of venous leg ulcers (VLUs) and diabetic foot ulcers (DFUs). The objective was to determine if TheraSkin could serve as a safe and effective alternative to bioengineered skin substitutes such as Apligraf(?) and Dermagraft(?). The authors conducted a retrospective study of 214 consecutive patients seen at the Inova Wound Center (Mt Vernon, Virginia), with either a DFU or a VLU. After excluding patients who did not meet the study criteria, the final eligible cohort consisted of 188 subjects, with 134 VLUs and 54 DFUs. Multivariate logistic regression was used to evaluate the relationship between baseline wound size and the proportion of healed wounds after 12 and 20 weeks from initial allograft application. The authors found that by the 12th week, DFUs closed 60.38% of the time and VLUs closed 60.77% of the time. After 20 weeks, the number of closed DFUs increased to 74.1% and the number of VLUs increased to 74.6%. The mean wound size in the DFU group was 6.2 cm(2) (±11.8) and 11.8 cm(2) (±22.5) in the VLU group. The mean number of TheraSkin allografts required ranged from 1 to 8, with an average of 2.03 (±1.47) at the 12-week point and an average of 3.23 (±2.77) at the 20-week point. Multivariate logistic regression was used to calculate the odds of wound healing by week 12 and week 20 in each group. The authors also analyzed adverse events and found TheraSkin to be noncontributory to any adverse events, verifying the safety of TheraSkin in this study population. In this study, TheraSkin has been shown to be highly effective for the treatment of both VLUs and DFUs with an acceptable safety profile.