Matthew John Taylor

Hypoxia-inducible factor (HIF), a key modulator of the transcriptional response to hypoxia, is increased in colon cancer. However, the role of HIF in colon carcinogenesis in vivo remains unclear. In this study, we found that intestinal epithelium-specific disruption of the von Hippel–Lindau tumor suppressor protein (VHL) resulted in constitutive HIF signaling, and increased HIF expression augmented colon tumorigenesis in the Apcmin/+ intestinal tumor model. Intestine-specific disruption of Vhl increased colon tumor multiplicity and progression from adenomas to carcinomas. These effects were ameliorated in mice with double disruption of Vhl and HIF-2α. Activation of HIF signaling resulted in increased cell survival in normal colon tissue; however, tumor apoptosis was not affected. Interestingly, a robust activation of cyclin D1 was observed in tumors of Apcmin/+ mice in which HIF-2α was activated in the intestine. Consistent with this result, bromodeoxyuridine incorporation indicated that cellular proliferation was increased in colon tumors following HIF activation. Further analysis showed that dysregulation of the intestinal iron absorption transporter divalent metal transporter-1 (DMT-1) was a critical event in HIF-2α–mediated colon carcinogenesis. These data provide a mechanistic basis for the widely reported link between iron accumulation and colon cancer risk. Together, our findings show that a chronic increase in HIF-2α in the colon initiates protumorigenic signaling, which may have important implications in developing preventive and therapeutic strategies for colon cancer. Cancer Res; 72(9); 2285–93. ©2012 AACR.

Hypoxia-inducible factor (HIF), a key modulator of the transcriptional response to hypoxia, is increased in colon cancer. However, the role of HIF in colon carcinogenesis in vivo remains unclear. In this study, we found that intestinal epithelium-specific disruption of the von Hippel–Lindau tumor suppressor protein (VHL) resulted in constitutive HIF signaling, and increased HIF expression augmented colon tumorigenesis in the Apcmin/+ intestinal tumor model. Intestine-specific disruption of Vhl increased colon tumor multiplicity and progression from adenomas to carcinomas. These effects were ameliorated in mice with double disruption of Vhl and HIF-2α. Activation of HIF signaling resulted in increased cell survival in normal colon tissue; however, tumor apoptosis was not affected. Interestingly, a robust activation of cyclin D1 was observed in tumors of Apcmin/+ mice in which HIF-2α was activated in the intestine. Consistent with this result, bromodeoxyuridine incorporation indicated that cellular proliferation was increased in colon tumors following HIF activation. Further analysis showed that dysregulation of the intestinal iron absorption transporter divalent metal transporter-1 (DMT-1) was a critical event in HIF-2α–mediated colon carcinogenesis. These data provide a mechanistic basis for the widely reported link between iron accumulation and colon cancer risk. Together, our findings show that a chronic increase in HIF-2α in the colon initiates protumorigenic signaling, which may have important implications in developing preventive and therapeutic strategies for colon cancer. Cancer Res; 72(9); 2285–93. ©2012 AACR.

There are sparse hydrogeological data and insufficient hydrogeological knowledge in many areas of the world reliant on groundwater. Nicaragua’s Pacific coast is one such region that is also experiencing water scarcity resulting from increasing demand on groundwater resources and climate change. The primary source of water in the region is the aquifer system associated with the Brito Formation, which is a marine sedimentary stratum of mostly sandstone that blankets 75 km of coastline in southwest Nicaragua. This study focused on the Tola municipality with the objective to advance a conceptual understanding of the hydrogeology and to support sustainable water development. Results demonstrate a heterogeneous aquifer system with regional flow characteristics and other factors that influence groundwater availability and water quality. Primary porosity is low, and secondary porosity is the primary mechanism of aquifer storage and is influenced by geological structure and diagenesis processes. Groundwater recharge is spatially and temporally heterogeneous and direct recharge is low. Infiltration of streamflow and runoff, especially early in the rainy season, is thought to be a large component of groundwater recharge. Climate, flow and recharge dynamics, and low storage capacity make the Brito Formation a sensitive resource and vulnerable to drought, increased abstraction, and climate change. This assessment provides data and insights useful for informing future studies and investments within the region and may be applicable in other Central American and Caribbean nations with coastal sandstone aquifers.

Background: There is a pressing need for new classes of treatment for psychosis. A key therapeutic target for novel compounds is the NMDA receptor, which may be modulated by nitric oxide donors such as sodium nitroprusside (SNP). Recent studies of SNP in patients with psychosis have mixed results, and the drug has to be administered intravenously. Glyceryl trinitrate (GTN) is a well-established cardiovascular medicine that is also a nitric oxide donor, and can be given orally. Aims: We explored the safety and potential effects of GTN in unmedicated patients with a first episode of psychosis. Methods: This was a single-centre, randomised, double-blind, placebo-controlled trial from December 2016 to April 2019 (ClinicalTrials.gov identifier: NCT02906553). Patients received 3 × sprays of GTN or placebo for three consecutive days, and were re-assessed on Days 1, 2, 3 and 7. The primary outcome was cognition (Jumping to Conclusions task), secondary outcomes were symptoms (Positive and Negative Syndrome Scale (PANSS)), verbal memory (Hopkins Verbal Learning task), and mood (Bond–Lader Visual Analogue Scales). Results: Nineteen patients were randomised, and 13 participants were included in the analyses. Compared with placebo, GTN was well tolerated, but was not associated with significant effects on cognition, symptoms, or mood. Bayesian statistics indicate that our results were 2× more likely under the null hypothesis than the alternative hypothesis, providing anecdotal evidence that GTN does not improve psychotic symptoms. Conclusions: We found no indication of an effect of GTN on symptoms of psychosis or cognition.

Ketamine hydrochloride was first synthesized in 1962.¹ It is a phencyclidine derivative that acts on the glutamate system by antagonizing N-methyl-D-aspartate (NMDA) receptors.¹ Ketamine has been used to model the symptoms of schizophrenia and is used in the treatment of severe depression and pain management² as well as being used recreationally. Misuse can be hazardous, leading to drug addiction.