Cell-Autonomous and Non-Autonomous Roles for TGF-beta Signaling in Pancreatic Cancer Metastasis

Pancreatic cancer is an almost universally lethal disease, with five-year survival rates approaching 6%. Its dismal prognosis is a consequence of several factors, including a lack of early detection methods, the inherent aggressive nature of this disease, and largely ineffective therapeutic regimens. Moreover, an overwhelming majority of patients are diagnosed at an advanced stage after their tumor has already metastasized. Decades of research have shed light onto the genes and signaling pathways that drive pancreatic carcinogenesis and progression. The transforming growth factor-beta (TGFβ) signaling pathway is often perturbed in pancreatic cancer, with alterations to the key transcription factor SMAD4 being observed in over half of all tumors. Paradoxically, TGFβ exerts both tumor suppressive and tumor-promoting influences. TGFβ suppresses tumor formation by regulating cell cycle progression and promoting apoptosis. However, it can also promote tumor progression by both cell autonomous and non-autonomous signaling mechanisms, namely, by promoting epithelial-mesenchymal transition, stromal deposition, and immune evasion. In pancreatic cancer, SMAD4 loss portends a worse prognosis and is correlated with widely metastatic disease. The goal of this thesis was to further understand the relationship between TGFβ signaling and metastatic efficiency in pancreatic cancer, with a particular interest on how TGFβ signaling in the tumor epithelium influences the tumor microenvironment. Using a novel conditional mouse model of pancreatic cancer, we show that reduced TGFβ signaling in invasive PDA results in the oligometastatic phenotype whereas oncogenic TGFβ signaling promotes widely metastatic disease. Additionally, inactivation of either TGFβR2 or SMAD4 in pancreatic cancer cells alters the immune response in invasive disease by mediating the accumulation of regulatory immune cell subsets. It will be important to further investigate how TGFβ signaling facilitates the recruitment and polarization of these cells into tumors and the extent to which it influences their function in order to fully appreciate their contributions to progression and metastasis in pancreatic cancer

Annual Greenland accumulation rates (2009–2012) from airborne snow radar

Contemporary climate warming over the Arctic is accelerating mass loss from the Greenland Ice Sheet through increasing surface melt, emphasizing the need to closely monitor its surface mass balance in order to improve sea-level rise predictions. Snow accumulation is the largest component of the ice sheet's surface mass balance, but in situ observations thereof are inherently sparse and models are difficult to evaluate at large scales. Here, we quantify recent Greenland accumulation rates using ultra-wideband (2–6.5 GHz) airborne snow radar data collected as part of NASA's Operation IceBridge between 2009 and 2012. We use a semiautomated method to trace the observed radiostratigraphy and then derive annual net accumulation rates for 2009–2012. The uncertainty in these radar-derived accumulation rates is on average 14 %. A comparison of the radar-derived accumulation rates and contemporaneous ice cores shows that snow radar captures both the annual and long-term mean accumulation rate accurately. A comparison with outputs from a regional climate model (MAR) shows that this model matches radar-derived accumulation rates in the ice sheet interior but produces higher values over southeastern Greenland. Our results demonstrate that snow radar can efficiently and accurately map patterns of snow accumulation across an ice sheet and that it is valuable for evaluating the accuracy of surface mass balance models

North-east sector of the Greenland Ice Sheet to undergo the greatest inland expansion of supraglacial lakes during the 21st century

The formation and rapid drainage of supraglacial lakes (SGL) influences the mass balance and dynamics of the Greenland Ice Sheet (GrIS). Although SGLs are expected to spread inland during the 21st century due to atmospheric warming, less is known about their future spatial distribution and volume. We use GrIS surface elevation model and regional climate model outputs to show that at the end of the 21st century (2070-2099) approximately 9.8 ± 3.9 km3 (+113% compared to 1980-2009) and 12.6 ± 5 km3 (+174%) of meltwater could be stored in SGLs under moderate (RCP 4.5) and high (RCP 8.5) climate change scenarios respectively. The largest increase is expected in the north-eastern sector of the GrIS (191% in RCP 4.5 and 320% in RCP 8.5), whereas in west Greenland, where the most SGLs are currently observed, the future increase will be relatively moderate (55% in RCP 4.5 and 68% in RCP 8.5)

High Rate of Hypothyroidism in Multidrug-Resistant Tuberculosis Patients Co-Infected with HIV in Mumbai, India.

Adverse events (AEs) among HIV-infected patients with multidrug-resistant tuberculosis (MDR-TB) receiving anti-TB and antiretroviral treatments (ART) are under-researched and underreported. Hypothyroidism is a common AE associated with ethionamide, p-aminosalicylic acid (PAS), and stavudine. The aim of this study was to determine the frequency of and risk factors associated with hypothyroidism in HIV/MDR-TB co-infected patients

How Much, How Fast?: A Review and Science Plan for Research on the Instability of Antarctica’s Thwaites Glacier in the 21st century

Constraining how much and how fast the West Antarctic Ice Sheet (WAIS) will change in the coming decades has recently been identified as the highest priority in Antarctic research (National Academies, 2015). Here we review recent research on WAIS and outline further scientific objectives for the area now identified as the most likely to undergo near-term significant change: Thwaites Glacier and the adjacent Amundsen Sea. Multiple lines of evidence point to an ongoing rapid loss of ice in this region in response to changing atmospheric and oceanic conditions. Models of the ice sheet's dynamic behavior indicate a potential for greatly accelerated ice loss as ocean-driven melting at the Thwaites Glacier grounding zone and nearby areas leads to thinning, faster flow, and retreat. A complete retreat of the Thwaites Glacier basin would raise global sea level by more than three meters by entraining ice from adjacent catchments. This scenario could occur over the next few centuries, and faster ice loss could occur through processes omitted from most ice flow models such as hydrofracture and ice cliff failure, which have been observed in recent rapid ice retreats elsewhere. Increased basal melt at the grounding zone and increased potential for hydrofracture due to enhanced surface melt could initiate a more rapid collapse of Thwaites Glacier within the next few decades

Pathways to understanding the genomic aetiology of osteoarthritis

Osteoarthritis is a common, complex disease with no curative therapy. In this review, we summarize current knowledge on disease aetiopathogenesis and outline genetics and genomics approaches that are helping catalyse a much-needed improved understanding of the biological underpinning of disease development and progression

Glacier-bed geomorphic processes and hydrologic conditions relevant to nuclear waste disposal

Characterizing glaciotectonic deformation, glacial erosion and sedimentation, and basal hydrologic conditions of ice sheets is vital for selecting sites for nuclear waste repositories at high latitudes. Glaciotectonic deformation is enhanced by excess pore pressures that commonly persist near ice sheet margins. Depths of such deformation can extend locally to a few tens of meters, with depths up to approximately 300 m in exceptional cases. Rates of glacial erosion are highly variable (0.05–15 mm a−1), but ratesa−1 are expected in tectonically quiescent regions. Total erosion probably not exceeding several tens of meters is expected during a glacial cycle, although locally erosion could be greater. Consolidation of glacial sediments that is less than expected from independent estimates of glacier thickness indicates that heads at the bases of past ice sheets were usually within 30% of the floatation value. This conclusion is reinforced by direct measurements of water pressure beneath portions of the West Antarctic ice sheet, which indicate average headsbed, despite thick ice at subfreezing temperatures. Therefore, in models of subglacial groundwater flow used to assess sites for nuclear waste repositories, a flux upper boundary condition based on water input from only basal melting will be far more uncertain than applying a hydraulic head at the upper boundary set equal to a large fraction of the floatation value

Exploring the ingredients required to successfully model the placement, generation, and evolution of ice streams in the British-Irish Ice Sheet

Ice stream evolution is a major uncertainty in projections of the future of the Greenland and Antarctic Ice sheets. Accurate simulation of ice stream evolution requires an understanding of a number of “ingredients” that control the location and behaviour of ice stream flow. Here, we test the influence of geothermal heat flux, grid resolution, and bed hydrology on simulated ice streaming. The palaeo-record provides snapshots of ice stream evolution, with a particularly well constrained ice sheet being the British-Irish Ice Sheet (BIIS). We implement a new basal sliding scheme coupled with thermo-mechanics into the BISICLES ice sheet model, to simulate the evolution of the BIIS ice streams. We find that the simulated location and spacing of ice streams matches well with the empirical reconstructions of ice stream flow in terms of position and direction when simple bed hydrology is included. We show that the new basal sliding scheme allows the accurate simulation for the majority of BIIS ice streams. The extensive empirical record of the BIIS has allowed the testing of model inputs, and has helped demonstrate the skill of the ice sheet model in simulating the evolution of the location, spacing, and migration of ice streams through millennia. Simulated ice streams also prompt new empirical mapping of features indicative of streaming in the North Channel region. Ice sheet model development has allowed accurate simulation of the palaeo record, and allows for improved modelling of future ice stream behaviour