Adenocarcinoma with signet ring cell (SRC) features has been reported to be a poor prognostic marker in gastric and colorectal carcinomas. Although uncommon in the esophagus, SRC histology, ...interestingly, has been correlated with improved survival. Our impression has been that the incidence of esophageal adenocarcinomas with SRC features is increasing and is associated with worse outcomes. We hypothesize that patients with SRC histology present with more advanced disease, respond less well to induction therapy, and have decreased survival after resection compared with patients with non-SRC adenocarcinoma.
The medical records of 151 consecutive patients who underwent resection for adenocarcinoma of the esophagus or gastroesophageal junction in a prospectively maintained database from 1998 to 2011 were reviewed. Outcomes of 23 patients (15%) with SRC histology (21 men, 2 women; average age, 66 years) were compared with 128 patients (85%) with non-SRC adenocarcinoma (116 men, 12 women; average age, 63 years). Overall survival, stage-specific survival, and response to induction therapy were evaluated. Cox regression multivariate analysis was used to identify independent predictors of 3-year survival.
SRC and non-SRC patients were evenly matched for clinical and tumor characteristics. Downstaging achieved with induction therapy was 13.3% (2 of 15) in SRC histology patients vs 67.1% (53 of 79) in non-SRC patients (p ≤ 0.001). Patients with SRC histology who did not respond well to induction treatment demonstrated strong trends toward a worse 3-year survival than patients with non-SRC adenocarcinoma (p = 0.084). The overall 3-year survival was 65.6% in patients without SRC histology vs 34.8% in those with SRC (p = 0.006). Patients with pathologic stage II or III and SRC histology had a 3-year survival of 27.3% compared with 57.4% in patients with non-SRC adenocarcinoma (p = 0.01). Multivariate analysis showed SRC histology trended toward significance as an independent risk factor for poor survival (p = 0.060).
Patients with adenocarcinoma of the esophagus or gastroesophageal junction and SRC histology respond less well to induction therapy and have decreased overall survival compared with patients with non-SRC histology.
Recent work has shown that nitric oxide (NO) acts as an important mediator of the effects of proinflammatory cytokines and mechanical strain in bone. Although several bone‐derived cells have been ...shown to produce NO in vitro, less is known about the isoforms of NO synthase (NOS), which are expressed in bone or their cellular distribution. Here we investigated the expression, cellular localization, and regulation of NOS mRNA and protein in cultured bone‐derived cells and in bone tissue sections. We failed to detect inducible NOS (iNOS) protein in normal bone using immunohistochemical techniques, even though low levels of iNOS mRNA were detected by sensitive reverse transcribed polymerase chain reaction (RT‐PCR) assays in RNA extracted from whole bone samples. Cytokine stimulation of bone‐derived cells and bone explant cultures caused dramatic induction of iNOS mRNA and protein in osteoblasts and bone marrow macrophages, but no evidence of iNOS expression was seen in osteoclasts by immunohistochemistry or in situ hybridization. Endothelial NOS (ecNOS) mRNA was also detected by RT‐PCR in whole bone, and immunohistochemical studies showed widespread ecNOS expression in bone marrow cells and trabecular lining cells in vivo. Related studies in vitro confirmed that ecNOS was expressed in cultured osteoblasts, stromal cells, and osteoclasts. Neuronal NOS mRNA was detected by RT‐PCR in whole bone, but we were unable to detect nNOS protein in bone cells in vivo or in studies of cultured bone‐derived cells in vitro. In summary, our data show that mRNAs for all three NOS isoforms are expressed in bone and provide evidence for differential expression and regulation of the enzymes in different cell types. These findings confirm the likely importance of the L‐arginine–NO pathway as a physiological mediator of bone cell function and demonstrate that it may be possible to exert differential effects on osteoblast and osteoclast activity in vivo by differential targeting of constitutive and inducible NOS isoforms by selective NOS inhibitors.
Mammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ...ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway in Drosophila. To investigate a possible role of UBR5 in regulation of the musculoskeletal system through modulation of mammalian HH signaling, we created a mouse model for specific loss of Ubr5 function in limb bud mesenchyme. Our findings revealed a role for UBR5 in maintaining cartilage homeostasis and suppressing metaplasia. Ubr5 loss of function resulted in progressive and dramatic articular cartilage degradation, enlarged, abnormally shaped sesamoid bones and extensive heterotopic tissue metaplasia linked to calcification of tendons and ossification of synovium. Genetic suppression of smoothened (Smo), a key mediator of HH signalling, dramatically enhanced the Ubr5 mutant phenotype. Analysis of HH signalling in both mouse and cell model systems revealed that loss of Ubr5 stimulated canonical HH-signalling while also increasing PKA activity. In addition, human osteoarthritic samples revealed similar correlations between UBR5 expression, canonical HH signalling and PKA activity markers. Our studies identified a crucial function for the Ubr5 gene in the maintenance of skeletal tissue homeostasis and an unexpected mode of regulation of the HH signalling pathway.
Large-scale molecular dynamics simulations are used to model the dewetting of solid surfaces by partially wetting thin liquid films. Two levels of solid−liquid interaction are considered that give ...rise to large equilibrium contact angles. The initial length and thickness of the films are varied over a wide range at the nanoscale. Spontaneous dewetting is initiated by removing a band of molecules either from each end of the film or from its center. As observed experimentally and in previous simulations, the films recede at an initially constant speed, creating a growing rim of liquid with a constant receding dynamic contact angle. Consistent with the current understanding of wetting dynamics, film recession is faster on the more poorly wetted surface to an extent that cannot be explained solely by the increase in the surface tension driving force. In addition, the rates of recession of the thinnest films are found to increase with decreasing film thickness. These new results imply not only that the mobility of the liquid molecules adjacent to the solid increases with decreasing solid−liquid interactions, but also that the mobility adjacent to the free surface of the film is higher than in the bulk, so that the effective viscosity of the film decreases with thickness.
Les statistiques precises sur les debarquements sont parmi les donnees les plus importantes pour la gestion des peches durables. Pour plusieurs peches, cependant, l'estimation des debarquements en ...fonction des especes et l'incertitude qui leur est associee peut s'averer difficile, particulierement dans le cas de peches complexes et multispecifiques. Nous mettons au point ici des methodes generales et flexibles pour estimer les debarquements en fonction des especes, a cause de notre interet pour la peche multispecifique des poissons de fond de la Californie. Nous decrivons des modeles bayesiens generalises lineaires et hierarchiques pour estimer la composition en especes a partir de donnees d'echantillonnage dans les ports; nous illustrons l'utilisation de chacun des modeles avec plusieurs exemples provenant des peches de Californie. Notre methodologie de modelisation hierarchique fournit un cadre statistiquement coherent qui peut produire des estimations des debarquements ainsi que de l'incertitude dans les cas de donnees d'echantillonnage rares ou manquantes; elle sert donc de complement aux procedures actuelles d' estimation des debarquements. De plus, nos methodes fournissent des facons de comparer les differentes formulations des modeles et de maintenir les estimations de l' incertitude lorsque les debarquements sont repartis de maniere contagieuse aux echelles temporelles ou spatiales. Notre structure de modelisation peut s'appliquer aux peches a l' echelle mondiale.
The purpose of this study was to assess the impact of anti-adenovirus neutralizing antibodies (AdNAbs) on the distribution, tolerability, and efficacy of intravenously administered oncolytic ...adenovirus. A translational model was developed to evaluate the impact of humoral immunity on intravenous administration of oncolytic adenovirus in humans.
Initially, severe combined immunodeficient (SCID)/beige mice were passively immunized with various amounts of human sera to establish a condition of preexisting humoral immunity similar to humans. A replication-deficient adenovirus encoding beta-galactosidase (rAd-betagal) was injected intravenously into these mice. An AdNAb titer that mitigated galactosidase transgene expression was determined. A xenograft tumor-bearing nude mouse model was developed to assess how a similar in vivo titer would impact the activity of 01/PEME, an oncolytic adenovirus, after intravenous administration.
In SCID/beige mice, there was a dose dependence between AdNAbs and galactosidase transgene expression; 90% of transgene expression was inhibited when the titer was 80. A similar titer reconstituted in the nude mice with human serum, as was done in the SCID/beige mice, did not abrogate the antitumor efficacy of the replicating adenovirus after intravenous administration. Viral DNA increased in tumors over time.
In intravenous administration, preexisting AdNAb titer of 80 significantly attenuated the activity of a 2.5 x 10(12) particles per kilogram dose of nonreplicating adenovirus; the same titer had no affect on the activity of an equivalent dose of replicating adenovirus. Our results suggest that a majority of patients with preexisting adenovirus immunity would be candidates for intravenous administration of oncolytic adenovirus.
Diffuse pulmonary neuroendocrine cell hyperplasia (DIPNECH) is characterized by a diffuse hypertrophy of neuroendocrine cells along the distal bronchioles. This condition is characterized by ...obstructive lung physiology and the development of small carcinoid tumors. We present a case of DIPNECH in a patient undergoing surgery for a primary lung adenocarcinoma. Interestingly, the chest wall also demonstrated involvement of DIPNECH indicated by the presence of small carcinoid tumors. The absence of any lung carcinoid tumor greater than 5 mm and the absence of lymph node metastases render the chest wall involvement unlikely to represent metastatic disease.
PDF
