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Purpose: Operable thoracic esophageal/gastroesophageal junction carcinoma (EC) is often treated with chemoradiation and surgery but tumor responses are unpredictable and heterogeneous. We hypothesized that aldehyde dehydrogenase-1 (ALDH-1) could be associated with response. Methods: The labeling indices (LIs) of ALDH-1 by immunohistochemistry in untreated tumor specimens were established in EC patients who had chemoradiation and surgery. Univariate logistic regression and 3-fold cross validation were carried out for the training (67% of patients) and validation (33%) sets. Non-clinical experiments in EC cells were performed to generate complimentary data. Results: Of 167 EC patients analyzed, 40 (24%) had a pathologic complete response (pathCR) and 27 (16%) had an extremely resistant (exCRTR) cancer. The median ALDH-1 LI was 0.2 (range, 0.01 to 0.85). There was a significant association between pathCR and low ALDH-1 LI (p=<0.001; odds-ratio [OR]=0.432). The 3-fold cross validation led to a concordance index (C-index) of 0.798 for the fitted model. There was a significant association between exCRTR and high ALDH-1 LI (p=<0.001; OR=3.782). The 3-fold cross validation led to the C-index of 0.960 for the fitted model. In several cell lines, higher ALDH-1 LIs correlated with resistant/aggressive phenotype. Cells with induced chemotherapy resistance upregulated ALDH-1 and resistance conferring genes (SOX9 and YAP1). Sorted ALDH-1+ cells were more resistant and had an aggressive phenotype in tumor spheres than ALDH-1− cells. Conclusions: Our clinical and non-clinical data demonstrate that ALDH-1 LIs are predictive of response to therapy and further research could lead to individualized therapeutic strategies and novel therapeutic targets for EC patients.

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Long-term potentiation (LTP) of parallel fiber-Purkinje cell (PF-PC) synapses in the cerebellum has been suggested to underlie aspects of motor learning. Previous in vitro studies have primarily used low frequency PF stimulation conditioning paradigms to generate either presynaptic PF-PC LTP (4-8 Hz) or postsynaptic PF-PC LTP (1 Hz). Little is known about the conditions that evoke PF-PC LTP in vivo. High frequency stimulation in vivo increases PC responsiveness to peripheral stimuli; however, neither the site of action nor the signaling pathways involved have been examined. Using flavoprotein autofluorescence optical imaging in the FVB mouse in vivo, this report describes that a conditioning stimulation consisting of a high frequency burst of PF stimulation (100 Hz, 15 pulse trains every 3 s for 5 min) evokes a long-term increase in the response to PF stimulation. Following the conditioning stimulation, the response to PF stimulation increases over 20 min to ∼130% above baseline and this potentiation persists for at least 2 h. Field potential recordings of the responses to PF stimulation show that the postsynaptic component is potentiated but the presynaptic, parallel fiber volley is not. Paired-pulse facilitation does not change after the conditioning stimulation, suggesting the potentiation occurs postsynaptically. Blocking non-NMDA (N-methyl-D-aspartic acid) ionotropic glutamate receptors with DNQX (6,7-dinitroquinoxaline-2,3-dione disodium salt, 50 μM, bath application) during the conditioning stimulation has no effect on the long-term increase in fluorescence. However, blocking subtype I metabotropic glutamate receptors (mGLuR 1 ) with LY367385 (200 μM) during the conditioning stimulation abolishes the long-term increase in fluorescence. Blocking GABAergic neurotransmission is not required to evoke this long-term potentiation. Blocking GABA A receptors reduces but does not eliminate the long-term potentiation. Therefore, this study demonstrates that high frequency PF stimulation generates long-term potentiation of PF-PC synapses in vivo. This novel form of LTP is generated primarily postsynaptically and is mediated by mGluR 1 receptors. Keywords synaptic plasticity; Purkinje cell; metabotropic glutamate receptors; flavoprotein imaging Synaptic plasticity in the cerebellar cortex and cerebellar nuclei has been widely viewed as a mechanism for the long-term storage of information and has been implicated as the neural substrate underlying various forms of motor learning (Ito, 2006;De Zeeuw and Yeo, 2005). At various synapses in the cerebellar cortex and cerebellar nuclei, several forms of synaptic plasticity have been described, including long-term depression (LTD) and long-term potentiation (LTP) (Hansel et al., 2001;Ito, 2001;Jorntell and Hansel, 2006). Of particular interest are the long-term changes occurring at parallel fiber (PF)-Purkinje cell (PC) synapses.

Background:Sunitinib is approved worldwide for treatment of advanced pancreatic neuroendocrine tumours (pNET), but no validated markers exist to predict response. This analysis explored biomarkers associated with sunitinib activity and clinical benefit in patients with pNET and carcinoid tumours in a phase II study.Methods:Plasma was assessed for vascular endothelial growth factor (VEGF)-A, soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, interleukin (IL)-8 (n=105), and stromal cell-derived factor (SDF)-1α (n=28). Pre-treatment levels were compared between tumour types and correlated with response, progression-free (PFS), and overall survival (OS). Changes in circulating myelomonocytic and endothelial cells were also analysed.Results:Stromal cell-derived factor-1α and sVEGFR-2 levels were higher in pNET than in carcinoid (P=0.003 and 0.041, respectively). High (above-median) baseline SDF-1α was associated with worse PFS, OS, and response in pNET, and high sVEGFR-2 with longer OS (P⩽0.05). For carcinoid, high IL-8, sVEGFR-3, and SDF-1α were associated with shorter PFS and OS, and high IL-8 and SDF-1α with worse response (P⩽0.05). Among circulating cell types, monocytes showed the largest on-treatment decrease, particularly CD14+ monocytes co-expressing VEGFR-1 or CXCR4.Conclusions:Interleukin-8, sVEGFR-3, and SDF-1α were identified as predictors of sunitinib clinical outcome. Putative pro-tumorigenic CXCR4+ and VEGFR-1+ monocytes represent novel candidate markers and biologically relevant targets explaining the activity of sunitinib.

This study considers the importance of lake trout habitat as a factor determining persistent organochlorine (OC) concentration. Lake trout is a stenothermal, cold water species and sensitive to hypoxia. Thus, factors such as lake depth, thermal stratification, and phosphorus enrichment may determine not only which lakes can support lake trout but may also influence among-lake variability in lake trout population characteristics including bioaccumulation of OCs. A survey of 23 lakes spanning much of the natural latitudinal distribution of lake trout provided a range of lake trout habitat to test the hypothesis that lake trout with greater access to littoral habitat for feeding will have lower concentrations of OCs than lake trout that are more restricted to pelagic habitat. Using the delta13C stable isotope signature in lake trout as an indicator of influence of benthic littoral feeding, we found a negative correlation between lipid-corrected delta13C and sigmaPCB concentrations supporting the hypothesis that increasing accessto littoral habitat results in lower OCs in lake trout. The prominence of mixotrophic phytoplankton in lakes with more contaminated lake trout indicated the pelagic microbial food web may exacerbate the biomagnification of OCs when lake trout are restricted to pelagic feeding. A model that predicted sigmaPCB in lake trout based on lake area and latitude (used as proximate variables for proportion of littoral versus pelagic habitat and accessibility to littoral habitat respectively) explained 73% of the variability in sigmaPCBs in lake trout in the 23 lakes surveyed.

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