Background Esophageal adenocarcinoma is often considered to arise from a clonal stem like population of cells, potentially responsible for its poor prognosis. TGF-β and Notch signaling pathways play important roles in regulating self-renewal of stem cells, cell-fate determination. Both pathways are frequently implicated in gastrointestinal carcinogenesis. However, their contributions to esophageal adenocarcinoma remain unclear. Methods We evaluated TGF-β and Notch signaling components in normal esophagus, Barrett's esophagus and adenocarcinoma tissues and cell lines by IHC and immunoblotting; Hes-1 transcription was assayed using a Hes-1 luciferase reporter. Results We demonstrate loss of Smad4 (p<0.05), and β2SP (p<0.01) in 5/10 Barrett's and 17/22 adenocarcinoma tissue sections. Concomitantly, dramatically raised levels of Notch signaling components Hes1 and Jagged1 occur in adenocarcinomas tissues and cell lines, compared to normal tissues. In normal esophagus, Oct3/4 positive cells are located in the basal layer (2-3 per cluster), representing a pool of progenitor cells. We observed an expansion of this pool of Oct3/4 positive cells in esophageal adenocarcinoma (15 per cluster). Furthermore, a panel of SOXs proteins documented for stem cell markers exhibit increased expression in tumor cells indicating expansion of putative cancer stem cells. Finally, we find growth inhibition in BE3 cells with a γ-secretase inhibitor (GSIXXI), but not in SKGT-4 cells. Unlike SKGT-4 cells, BE3 cells have activated Notch signaling with disruption of TGF-β signaling. Conclusions Our study demonstrates a potential therapeutic value for targeted therapy in esophageal adenocarcinoma in the setting of loss of β2SP/TGF-β with concomitant constitutively active Notch signaling.
DNA from the peripheral blood mononuclear cells of 17 different individuals infected with human T-cell lymphoma/leukemia virus type II (HTLV-II) was successfully amplified by the polymerase chain reaction (PCR) with the primer pair SK110/SK111. This primer pair is conserved among the pol genes of all primate T-cell lymphoma viruses (PTLV) and flanks a 140-bp fragment of DNA which, when used in comparative analyses, reflects the relative degree of diversity among PTLV genomes. Cloning, sequencing, and phylogenetic comparisons of these amplified 140-bp pol fragments indicated that there are at least two distinct genetic substrains of HTLV-II in the Western Hemisphere. These data were confirmed for selected isolates by performing PCR, cloning, and sequencing with up to 10 additional primer pair-probe sets specific for different regions throughout the PTLV genome. HTLV-II isolates from Seminole, Guaymi, and Tobas Indians belong in the new substrain of HTLV-II, while the prototype MoT isolate defines the original substrain. There was greater diversity among HTLV-II New World strains than among HTLV-I New World strains. In fact, the * Corresponding author.
Transforming growth factor beta (TGF-β) signaling has diverse and complex roles in various biological phenomena such as cell growth, differentiation, embryogenesis and morphogenesis. ES cells provide an essential model for understanding the role of TGF-β signaling in lineage specification and differentiation. Recent studies have suggested significant role of TGF-β in stem/progenitor cell biology. Here in this review, we focus on the role of the TGF-β superfamily in neuronal development.
PURPOSE: Perioperative orthopedic patients are at high risk for both venous thromboembolic (VTE) and non-VTE related clinical complications. Identifying a non-PE diagnosis to explain clinical decompensation may not adequately exclude a concurrent thromboembolic event in this specific population. METHODS:We gathered consecutive data retrospectively for all patients suspected of having a PE who received a CTPA scan from June 2013 until October 2014. Demographic data, presenting signs and symptoms, findings on CTPA including non-PE diagnoses, and survival to hospital discharge were recorded. Categorical variables were compared between groups (PE vs. non-PE) using chi-square test.RESULTS: Three hundred and seventy-two patients were scanned during the study period of which 67 (18%) were found to have PE. Baseline demographic and clinical data was similar between groups (age, gender, race, BMI, presence of prior DVT, presence of fracture). There was no difference between those found to have PE and not with regard to presence of chest pain, lower extremity edema, hypotension (systolic blood pressure < 100mmHg), or hypoxia (SpO2 <90%). Alternative radiographic findings on CTPA were common in both the PE and non-PE group; more than 50% of patients in both groups had atelectasis and 40% vs. 31% had pleural effusion in the PE and non-PE group, respectively. There was no difference in the VTE prophylactic agents used between groups. Overall, there was no significant difference in survival between groups (100% survival in PE group vs. 98.3% survival in non-PE group). CONCLUSIONS:Orthopedic patients frequently have both VTE and non-VTE perioperative complications that may mimic each other in their clinical presentation. Identifying PE in an orthopedic patient does not exclude additional concurrent pathologies that may have produced clinical decompensation.CLINICAL IMPLICATIONS: Clinicians should have a low threshold for diagnostic workup for PE in the orthopedic population even when an alternative etiology for cardio-respiratory compromise may be present. DISCLOSURE:The following authors have nothing to disclose:
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