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The original version of this Article contained an error in the title, which was incorrectly given as 'APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'. This has now been corrected in both the PDF and HTML versions of the Article to read 'A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'.

This work provides an architecture that incorporates depth and tactile information to create rich and accurate 3D models useful for robotic manipulation tasks. This is accomplished through the use of a 3D convolutional neural network (CNN). Offline, the network is provided with both depth and tactile information and trained to predict the object's geometry, thus filling in regions of occlusion. At runtime, the network is provided a partial view of an object. Tactile information is acquired to augment the captured depth information. The network can then reason about the object's geometry by utilizing both the collected tactile and depth information. We demonstrate that even small amounts of additional tactile information can be incredibly helpful in reasoning about object geometry. This is particularly true when information from depth alone fails to produce an accurate geometric prediction. Our method is benchmarked against and outperforms other visual-tactile approaches to general geometric reasoning. We also provide experimental results comparing grasping success with our method.

Background Checkpoint inhibitors (CPIs) have transformed treatment of many malignancies. However, to date, response to checkpoint blockade in unselected gastrointestinal (GI) cancers has been disappointing. Tumours which display a non-T-cell inflamed phenotype such as mismatch repair proficient (MMRp) oesophagogastric (OG) and colorectal cancers (CRC) respond less frequently to CPIs. Changes in tumour expression of antigens and increased immune infiltrate are associated with improved response to CPIs. Epigenetic modulation of tumours using HDAC inhibitors can lead to increased tumour antigen presentation, immune cell infiltrates and thereby may increase the chance of response to immunotherapy. Trial design EMERGE is designed to evaluate the safety and efficacy of domatinostat, a selective class 1 histone deacetylase inhibitor in combination with avelumab, an anti-PD-L1 monoclonal antibody in patients with previously treated, inoperable or metastatic MMRp OG and CRC. The trial is conducted in 2 stages: Phase IIA will establish a safe and tolerated dose of domatinostat plus avelumab using a 3 + 3 dose finding design and escalating doses of domatinostat will be examined, dosing of avelumab will remain constant. The phase IIB will use a Simon two stage optimal design to assess efficacy of the combination in achieving radiological response according to RECIST v1.1. The primary endpoint of the phase IIB is best objective response rate (ORR) at 6 months. To rule out an ORR of 5% in the CRC cohort, while aiming for 20%, 1/10 and 4/29 responses are required in the 1st and 2nd stages respectively. To rule out an ORR of 15% in the OG cohort while aiming for 35%, 2/9 and 9/34 responses are required in the 1st and 2nd stages respectively with a 1-sided alpha of 5% and 80% power. Secondary endpoints are DoOR, PFS, OS, DCR, safety and tolerability. Exploratory objectives will investigate dynamic changes in expression of tumour associated antigens and immune infiltrates in baseline and on-treatment biopsies and correlate baseline tumour characteristics and circulating biomarkers with tumour response and survival. Recruitment commenced in January 2019, 83 patients will be recruited over 3 years. (ClinTrials.gov. ID: NCT03812796). Legal entity responsible for the study Royal Marsden Hospital NHS Foundation Trust. Funding Royal Marsden Hospital NHS Foundation Trust, 4SC. Disclosure M. Hubank: Research grant / Funding (self), Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (self), Research grant / Funding (institution): Roche Diagnostics; Research grant / Funding (self), Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (self), Research grant / Funding (institution): Guardant Health; Research grant / Funding (self), Research grant / Funding (institution): Celgene; Research grant / Funding (self), Research grant / Funding (institution): Eli Lilley. I. Chau: Honoraria (self): Eli-Lilly; Research grant / Funding (institution): Eli-Lilly; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Bristol Meyers Squibb; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Roche; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Merck; Honoraria (self): Servier; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Servier. D. Cunningham: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): 4SC; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merck. All other authors have declared no conflicts of interest.

Temperature is the most influential climatic variable for flexible pavement design using a mechanistic-empirical approach. While the effect of climatic variables on pavement designs has bee...

Climate condition is an important factor that affects the performance of pavements and distress predictions using mechanistic-empirical analyses. This study aims to analyse the sensitivity of flexible pavement distress predictions to climatic inputs using the AASHTOWare Pavement ME Design software in the state of Michigan. Typical traffic parameters, pavement structures and material properties for the state of Michigan were used as inputs for the analysis of flexible pavement performance. Six representative sites geographically distributed throughout Michigan and two typical traffic levels (high and medium) were incorporated in a comprehensive analysis of the effects of climate on flexible pavement performance predictions. A normalised sensitivity index was adopted to quantitatively evaluate the sensitivity of distress predictions to the five individual climatic variables: temperature, wind speed, precipitation, percent sunshine and relative humidity. The results of this study showed that the pred...

Oesophageal and gastric adenocarcinoma (OGA) treatment remains challenging. Improvements in early diagnosis, staging and management might have contributed to survival prolongation. To examine this hypothesis, we assessed outcomes of resected OGA patients in our institution over 10 years, comparing two time periods, 2001–2005 and 2006–2010. Records from patients who had undergone surgery with radical intent and follow-up for OGA were retrospectively reviewed. Patients followed up at hospitals other than the Royal Marsden Hospital were excluded. Two different cohorts were identified: patients with oesophageal and type I or type II oesophagogastric junction (OGJ) tumours, and patients with gastric and type III OGJ tumours. We identified 360 patients: 147 from 2001–2005 and 213 from 2006–2010. The characteristics were comparable across the two time periods. Between 2001–2005 and 2006–2010, the percentage of R0 resections increased (from 67.1 to 81.1 % for proximal tumours and from 76.3 to 95.9 % for gastric and type III OGJ tumours). The mean number of lymph nodes retrieved increased over time. The 5-year overall survival rate increased significantly from 42.3 to 56.6 % for proximal tumours and from 38.8 to 55.3 % for gastric and type III OGJ tumours. Similarly, the disease-free survival rate significantly increased from 34.6 to 53.5 % for proximal tumours and from 35.9 to 51.1 % for gastric and type III OGJ tumours. This study comprehensively describes the improvement in survival outcomes in a major UK referral centre over a 10-year period, identifying potentially relevant factors such as increased number of R0 resections and higher lymph node yield.

In this work, we hypothesize that phosphorus (P) concentrations in streams vary seasonally and with streamflow and that it is important to incorporate this variation when predicting changes in P loading associated with climate change. Our study area includes 14 watersheds with a range of land uses throughout the U.S. Great Lakes Basin. We develop annual seasonal load-discharge regression models for each watershed and apply these models with simulated discharges generated for future climate scenarios to simulate future P loading patterns for two periods: 2046–2065 and 2081–2100. We utilize output from the Coupled Model Intercomparison Project phase 3 downscaled climate change projections that are input into the Large Basin Runoff Model to generate future discharge scenarios, which are in turn used as inputs to the seasonal P load regression models. In almost all cases, the seasonal load-discharge models match observed loads better than the annual models. Results using the seasonal models show that the concurrence of nonlinearity in the load-discharge model and changes in high discharges in the spring months leads to the most significant changes in P loading for selected tributaries under future climate projections. These results emphasize the importance of using seasonal models to understand the effects of future climate change on nutrient loads.

This article critically examines neo-republican democratic theory, as articulated by Philip Pettit, with respect to its capacity to address some of the pressing challenges of our times. While the neo-republican focus on domination has great promise, it mistakenly commits to the position that democracy—the primary tool with which we fight domination—is limited to state activity. Examining this error helps us make sense of two additional problems with his theory: an overestimation of the capacity of legislative bodies to identify sufficient responses to practices of domination, and the potential conflict between avoiding state domination of the general citizenry and avoiding state domination of a part of it. Minimizing domination is simply too demanding and complex a task for us to rely on one institutional structure, no matter how well designed, to accomplish.

Energy securities, increases in fossil fuel prices, and concern about climate change have been major causes of increased bioenergy production. Because biomass production is rural-based and generally labor-intensive, bioenergy development happens mainly in less developed countries. Comprehensive analysis is needed to develop appropriate policies to ensure the sustainability of resource use while promoting economic development. Given this, public policies must promote more efficient inter- and intra-sector water allocation schemes. Economic instruments, such as water pricing and water markets, can be used to avoid transferring negative environmental and economic impacts of meeting global renewable energy targets to production regions. In Brazil, water markets are not allowed, but the law has established raw water charges as a management instrument at the river basin level. However, the majority of bulk water charge systems have been defined exclusively for raising revenue. Integrated economic modeling can be a useful tool to support the design of effective economic instruments. This paper describes the main features of two economic modeling approaches that can support effective water pricing decisions. Three case studies illustrate sugarcane ethanol production river basins in Brazil where water prices have already been established but fail to reflect the real scarcity value of water in the region. In addition, preliminary results of a national-level economic model being built for Brazil show that increasing water charges for the agricultural sector can have significant effects on water demand and agriculture production. The potential benefits of water pricing policy decisions based on economic modeling results are assessed. © 2015 Society of Chemical Industry and John Wiley & Sons, Ltd

Many democratic and jurisprudential theorists have too often uncritically accepted Alexander Bickel's notion of “the countermajoritarian difficulty” when considering the relationship between judicial review and democracy; this is the case for arguments both for and against judicial review. This framework is both theoretically and empirically unsustainable. Democracy is not wholly synonymous with majoritarianism, and judicial review is not inherently countermajoritarian in the first place. In modern democratic political systems, judicial review is one of many potential veto points. Since all modern democratic political systems contain veto points, the relevant and unexplored question is what qualities might make a veto point relatively democratic.Proceeding on the assumption that democracy's primary normative value is found in its opposition to domination by both state and private actors, we make a preliminary effort to delineate what qualities a democratic veto point might have, identifying five criteria, and evaluate judicial review using these criteria. We conclude that judicial review's performance against these criteria is decidedly mixed, but in the final balance is likely to be a modest net positive for democracy, particularly when compared to other veto points commonly found in contemporary democratic political systems.

Large-scale bioenergy production will affect the hydrologic cycle in multiple ways, including changes in canopy interception, evapotranspiration, infiltration, and the quantity and quality of surface runoff and groundwater recharge. As such, the water footprints of bioenergy sources vary significantly by type of feedstock, soil characteristics, cultivation practices, and hydro-climatic regime. Furthermore, water management implications of bioenergy production depend on existing land use, relative water availability, and competing water uses at a watershed scale. This paper reviews previous research on the water resource impacts of bioenergy production-from plot-scale hydrologic and nutrient cycling impacts to watershed and regional scale hydro-economic systems relationships. Primary gaps in knowledge that hinder policy development for integrated management of water-bioenergy systems are highlighted. Four case studies in the Americas are analyzed to illustrate relevant spatial and temporal scales for impact assessment, along with unique aspects of biofuel production compared to other agroforestry systems, such as energy-related conflicts and tradeoffs. Based on the case studies, the potential benefits of integrated resource management are assessed, as is the need for further case-specific research.

Slow slip events (SSEs) observed in subduction zones around the world exhibit a wide range of recurrence intervals, durations, and propagation speeds. To illuminate possible mechanisms responsible for the observed variability and guide future modeling efforts, we employ the earthquake simulator RSQSim to explore the effects of variations in the convergence rates, frictional parameters, and effective normal stress on SSE characteristics. Both recurrence intervals and durations of SSEs are essentially directly proportional to the effective normal stress, while along-strike propagation speeds are inversely proportional. Effective normal stresses in the range of 3–9 MPa produce fault slip consistent with observed SSEs. Changes in rate-state frictional instability (b − a) have a moderate inverse effect on propagation speeds but much weaker effects on recurrence intervals and durations. Convergence rates are inversely proportional to recurrence intervals, propagation speeds show a weak positive relationship, and event durations appear insensitive.

In order to extend previous research on the twofold multidimensionality of academic self-concept (i.e. its domain-specific structure and separation into competence and affect components), the present study tests its generalisability among vocational students from mainland China. A Chinese version of self-description questionnaire I was administered to Year 1 secondary vocational students in three academic years (2006, 2007, 2008; N = 1053) measuring the self-concepts in Chinese (native language), English (non-native language), math and general school. Confirmatory factor analyses showed that models separating competence and affect components within each domain fitted better than pure domain-specific models. This pattern was consistent across the subsamples of students studying in the three academic years. Thus, the present findings support the generalisability of the twofold multidimensionality of academic self-concept to Chinese vocational students and to students’ native and non-native languages. Theore...

Pancreatic ductal adenocarcinoma (PDA) has a very poor prognosis. Treatment with FOLFIRINOX has been shown to improve outcomes, but can be associated with significant toxicity.A retrospective review was performed of all patients with locally advanced or metastatic PDA treated with FOLFIRINOX at the Royal Marsden between November 2010 and November 2013. Efficacy, tolerability, and potential prognostic factors were evaluated.Twenty-seven patients with metastatic PDA and 22 patients with locally advanced PDA were treated with FOLFIRINOX. Patients received a median of 9 cycles (range, 1-26) of FOLFIRINOX. The overall response rate was 41% (20 patients), and a further 17 patients (35%) had stable disease. Thirty-five patients (71%) received FOLFIRINOX in the first-line setting, with a median progression-free survival and overall survival, respectively, of 12.9 months and 18.4 months for patients with locally advanced disease; and 8.4 months and 12.2 months for patients with metastatic disease. The most frequently occurring Grade 3/4 toxicities were neutropenia (29%), fatigue (18%), febrile neutropenia (14%), thromboembolism (12%), and thrombocytopenia (10%). In a univariate analysis, reduction in CA 19-9 of50% (P .001), normalization of CA19-9 (P .001), surgery after FOLFIRINOX (P = .004), and use of prophylactic pegfilgrastim (P = .005) were prognostic for overall survival.The efficacy and tolerability of FOLFIRINOX for PDA at our institution is similar to that reported in clinical trials. Careful selection of patients and monitoring of response (according to CA19-9) and toxicities can help maximize advantage in this patient population.

Given the large share of the water budget contributed by evapotranspiration (ET), accurately estimating ET is critical for hydro-climate change studies. Routinely, hydrologic models use temperature proxy relationships to estimate potential evapotranspiration (PET) when forced using GCM/RCM projections of precipitation and temperature. A limitation of this approach is that the temperature proxy relationships do not account for the conservation of energy needed to estimate ET consistently in climate change scenarios. In particular, PET methods using temperature as a proxy fail to account for the negative feedback of ET on surface temperature. Using several GCM projections and a hydrologic model developed for the Great Lakes basin watersheds, the NOAA Large Basin Runoff Model (LBRM), the importance of maintaining a consistent energy budget in hydrologic and climate models is demonstrated by comparing runoff projections from temperature proxy and energy conservation methods. Differences in hydrologic responses are related to watershed characteristics, hydrologic model parameters and climate variables. It is shown that the temperature proxy approach consistently leads to prediction of relatively large and potentially unrealistic reductions in runoff. Therefore, hydrologic projections adhering to energy conservation principles are recommended for use in climate change impact studies.

Minimally invasive circulating free DNA (cfDNA) analysis can portray cancer genome landscapes but highly sensitive and specific genetic approaches are necessary to accurately detect mutations with often low variant frequencies. We developed a targeted cfDNA sequencing technology using novel off-the-shelf molecular barcodes for error correction, in combination with custom solution hybrid capture enrichment. Modelling based on cfDNA yields from 58 patients shows that our assay, which requires 25ng of cfDNA input, should be applicable to >95% of patients with metastatic colorectal cancer. Sequencing of a 163.3 kb target region including 32 genes detected 100% of single nucleotide variants with 0.15% variant frequency in cfDNA spike-in experiments. Molecular barcode error correction reduced false positive mutation calls by 98.6%. In a series of 28 patients with metastatic colorectal cancers, 80 out of 91 (88%) mutations previously detected by tumour tissue sequencing were called in the cfDNA. Call rates were similar for single nucleotide variants and small insertions/deletions. Mutations only called in cfDNA but not detectable in matched tumour tissue included, among others, a subclonal resistance driver mutation to anti-EGFR antibodies in theKRASgene, multiple activatingPIK3CAmutations in each of two patients (indicative of parallel evolution), andTP53mutations originating from clonal haematopoiesis. Furthermore, we demonstrate that cfDNA off-target read analysis allows the reconstruction of genome wide copy number aberration profiles from 71% of these 28 cases. This error-corrected ultra-deep cfDNA sequencing assay with a target region that can be readily customized enables broad insights into cancer genomes and evolution.

Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in RAS wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as RAS wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies. Significance: Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. Cancer Discov; 8(10); 1270–85. ©2018 AACR. See related commentary by Siravegna and Corcoran, p. 1213. This article is highlighted in the In This Issue feature, p. 1195

Inborn errors of cobalamin metabolism result in problems affecting multiple systems, including hematologic, neurologic, ophthalmologic, dermatologic, cardiovascular and renal. Exogenous cobalamin is internalized by carrier mediated endocytosis and converted to the active cobalamin derivatives adenosylcobalamin and methylcobalamin in the mitochondria and cytoplasm, respectively. In the past, most patients with inborn errors of cobalamin metabolism came to medical attention when they developed symptoms of their disorder. Mild methylmalonic aciduria occurs in patients with mutations affecting the methylmalonyl-CoA epimerase gene, which encodes methylmalonyl-CoA isomerase, the enzyme that catalyzes the step prior to mutase in propionyl-CoA metabolism. The cobalamin deficiency type C disorder is by far the most frequent cause of combined methylmalonic aciduria and homocystinuria. The methylmalonic aciduria type D and homocystinuria disorder was originally identified in 1970 in two brothers with combined methylmalonic aciduria and homocystinuria and relatively mild neurological problems.

This research develops an integrated methodology to determine the economic value to anglers of recreational fishery ecosystem services in Everglades National Park that could result from different water management scenarios. The study first used bio-hydrological models to link managed freshwater inflows to indicators of fishery productivity and ecosystem health, then link those models to anglers' willingness-to-pay for various attributes of the recreational fishing experience and monthly fishing effort. This approach allowed us to estimate the foregone economic benefits of failing to meet monthly freshwater delivery targets. The study found that the managed freshwater delivery to the Park had declined substantially over the years and had fallen short of management targets. This shortage in the flow resulted in the decline of biological productivity of recreational fisheries in downstream coastal areas. This decline had in turn contributed to reductions in the overall economic value of recreational ecosystem services enjoyed by anglers. The study estimated the annual value of lost recreational services at $68.81 million. The losses were greater in the months of dry season when the water shortage was higher and the number of anglers fishing also was higher than the levels in wet season. The study also developed conservative estimates of implicit price of water for recreation, which ranged from $11.88 per AF in November to $112.11 per AF in April. The annual average price was $41.54 per AF. Linking anglers' recreational preference directly to a decision variable such as water delivery is a powerful and effective way to make management decision. This methodology has relevant applications to water resource management, serving as useful decision-support metrics, as well as for policy and restoration scenario analysis.

High-value urban zones in coastal South Florida are considered particularly vulnerable to salt water intrusion into the groundwater-based, public water supplies caused by sea level rise (SLR) in combination with the low topography, existing high water table, and permeable karst substrate. Managers in the region closely regulate water depths in the extensive South Florida canal network to control closely coupled groundwater levels and thereby reduce the risk of saltwater intrusion into the karst aquifer. Potential SLR adaptation strategies developed by local managers suggest canal and groundwater levels may have to be increased over time to prevent the increased salt water intrusion risk to groundwater resources. However, higher canal and groundwater levels cause the loss of unsaturated zone storage and lead to an increased risk of inland flooding when the recharge from rainfall exceeds the capacity of the unsaturated zone to absorb it and the water table reaches the surface. Consequently, higher canal and groundwater levels are also associated with increased risk of economic losses, especially during the annual wet seasons. To help water managers and urban planners in this region better understand this trade-off, this study models the relationships between flood insurance claims and groundwater levels in Miami-Dade County. Via regression analyses, we relate the incurred number of monthly flood claims in 16 Miami-Dade County watersheds to monthly groundwater levels over the period from 1996 to 2010. We utilize these estimated statistical relationships to further illustrate various monthly flood loss scenarios that could plausibly result, thereby providing an economic quantification of a “too much water” trade-off. Importantly, this understanding is the first of its kind in South Florida and is exceedingly useful for regional-scale hydro-economic optimization models analyzing trade-offs associated with high water levels.

Hydro-climatic impacts in water resources systems are typically assessed by forcing a hydrologic model with outputs from general circulation models (GCMs) or regional climate models. The challenges of this approach include maintaining a consistent energy budget between climate and hydrologic models and also properly calibrating and verifying the hydrologic models. Subjective choices of loss, flow routing, snowmelt and evapotranspiration computation methods also increase watershed modelling uncertainty and thus complicate impact assessment. An alternative approach, particularly appealing for ungauged basins or locations where record lengths are short, is to predict selected streamflow quantiles directly from meteorological variable output from climate models using regional regression models that also include physical basin characteristics. In this study, regional regression models are developed for the western Great Lakes states using ordinary least squares and weighted least squares techniques applied to selected Great Lakes watersheds. Model inputs include readily available downscaled GCM outputs from the Coupled Model Intercomparison Project Phase 3. The model results provide insights to potential model weaknesses, including comparatively low runoff predictions from continuous simulation models that estimate potential evapotranspiration using temperature proxy information and comparatively high runoff projections from regression models that do not include temperature as an explanatory variable. Copyright © 2014 John Wiley & Sons, Ltd.

Circulating tumor cells (CTCs) have been found to be of clinical utility in predicting response to treatment and prognosis in several malignancies. Less is known of the prevalence and clinical relevance of CTCs in esophagogastric adenocarcinoma, with the available data arising from heterogeneous patient populations using varied detection methods.A pilot study was undertaken to assess the prevalence of CTCs in patients with advanced esophageal or gastric adenocarcinoma. Patients were eligible if they had advanced disease and either had received no prior therapy or had progressed after prior chemotherapy. Blood samples for CTC analysis were obtained at baseline and during the course of treatment. The CellSearch immunomagnetic CTC detection platform was used.Twenty-two patients with metastatic esophageal or gastric adenocarcinoma were enrolled. Eighteen received first-line EOX (epirubicin/oxaliplatin/capecitabine) chemotherapy (± panitumumab) and had baseline samples suitable for CTC analysis. At baseline, ≥ 2 CTCs were detected in 8 patients (44%). Overall tumor response rate was 60% in patients with2 CTCs and 37.5% in patients with ≥ 2 CTCs. Median progression-free and overall survival were 6.1 and 10.5 months and 5.2 and 6.1 months in the groups of patients with2 CTCs and ≥ 2 CTCs, respectively. The study was prematurely discontinued, owing to the withdrawal of commercial support.The incidence of CTCs in locally advanced or metastatic esophagogastric cancer may be clinically relevant. Investigation of the potential clinical utility of CTCs is warranted in a larger cohort of patients with esophagogastric cancer.

We examined how achievement (mastery and performance) and social goals (affiliation, approval, concern, and status) influenced various learning outcomes in two collectivist cultures. Filipino (n $$\,=\,$$ 355) and Hong Kong Chinese (n $$\,=\,$$ 697) secondary students answered the relevant questionnaires. Regression analyses using mastery, performance, and social goals as predictors and learning outcomes as criterion variables were done separately for the HK and Filipino samples. Results indicated that the all the social goals were positively associated with adaptive learning. Mastery goal emerged as a positive predictor of deep learning and self-regulation across both contexts. To understand the relative importance of different goals, causal dominance analysis was used. Different types of goals were causally dominant for the HK and Filipino students. Implications and directions for future research are discussed.

There has been growing interest in the impact of land-use regulation and planning on housing development and markets, and a consequent search for quantified measures of their extent and efficacy. Nevertheless, despite the UK having a long-established and comprehensive planning system, this kind of quantitative analysis of system performance has been limited. This paper assembles and reports on a set of local-level measures for England for the late 2000s and assesses their effectiveness in predicting the key flow-of-consents measure and actual housing development. The pattern of restrictiveness is assessed against broad sustainability criteria including urban settlement structure, economic growth potential, and housing affordability and need. We also assess recent changes and the potential impact of a major system change towards more localised planning decision making. Keywords: planning, housing, restrictiveness measures, localisation, England

Flood risk assessment in many locations, especially in low-income countries, is severely hindered by a lack of hydrologic data. This study illustrates the application of regional rainfall frequency analysis, combined with ungauged basin analysis, to estimate flood discharges in the Gonaives basin in Haiti. Using limited daily rainfall data from seven gauges within and near the watershed, a regional extreme value distribution is selected and design storms are developed. These design storms are then input to a rainfall-runoff model, the parameters of which are estimated from spatial analysis of physical watershed characteristics. As a case study, the flood discharge and associated return period are estimated for the 2004 event that claimed 1,650 lives, and model outputs for other synthetic design storms are compared with large observed floods in other Caribbean basins similar in size to the Gonaives basin. Results of the comparative analysis indicate that the simulated peak flood flows of the Gonaiv...

Background ICONIC is a single arm phase 2 trial investigating the safety and efficacy of 4 cycles pre-operative and 4 cycles post-operative FLOT-A in resectable OGA. We report results from the safety run-in phase and early translational biomarker data. Methods Eligible pts were enrolled into the 3 + 3 design dose finding stage. Standard dose FLOT was administered with 10mg/kg iv avelumab q2 weeks (dose level 0). Dose limiting toxicities (DLTs) were assessed for 28d. Biopsies were taken at baseline and post cycle 2. Results At data cut-off (12/4/19) 6 pts were enrolled and completed pre-operative treatment. 1/6 pts experienced a DLT (chest pain during 5FU infusion), and dose level 0 was established as the safe dose for the efficacy stage of the trial. During pre-operative FLOT-A all pts experienced at least one grade 1-2 adverse event (AE), most commonly diarrhoea (5/6 pts), fatigue, nausea, peripheral neuropathy and hypokalaemia (all 4/6 pts); 3/6 pts experienced at least one grade 3-4 AE: neutropenia and elevated liver enzymes (1 pt), thrombotic event (1 pt) and cardiac chest pain (1 pt). 4/6 pts reported any grade chest pain and underwent cardiac work up: 1 episode was due to PE, 1 of likely GI origin and 2 cardiac in nature, which then recurred in one pt who was re-exposed to FLOT without avelumab. 3/6 pts completed 4 cycles pre-operative FLOT-A: 1 pt discontinued avelumab due to diarrhoea, 2 pts discontinued FLOT-A due to cardiac chest pain and switched to a regimen without 5FU. 5 pts have undergone surgery at data cut-off, without unexpected complications. Immunofluorescence shows changes of CD8-, memory- and regulatory T cell infiltrates between baseline and on-treatment biopsies, and detailed results will be presented. Conclusions This is the first data showing that FLOT can be combined with a PD-L1-inhibitor with FLOT-A having a manageable safety profile at dose level 0 (standard dose FLOT + 10mg/kg avelumab). As chest pain of variable aetiologies was observed in 4/6 patients this will be closely monitored and assessed during the efficacy phase. No unexpected complications have been observed during surgery following FLOT-A treatment. Clinical trial identification 2016-003306-13. Legal entity responsible for the study Royal Marsden Hospitals NHS Foundation Trust. Funding Royal Marsden Hospital NHS Foundation Trust Institute of Cancer Research, Merck Pharmaceuticals. Disclosure M. Davidson: Travel / Accommodation / Expenses: Celgene. N. Starling: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck; Honoraria (institution): AstraZeneca. I. Chau: Advisory / Consultancy: Eli-Lilly; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): Eli-Lilly; Research grant / Funding (institution): Janssen Cilag; Research grant / Funding (institution): Sanofi Oncology; Research grant / Funding (institution): Merck-Serono; Honoraria (institution): Eli-Lilly. D. Cunningham: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck-Serono; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Merrimack; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi. D. Morganstein: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Roche. M.D. Forster: Research grant / Funding (institution): Merck; Honoraria (institution): Merck. M. Gerlinger: Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS. All other authors have declared no conflicts of interest.

Gastrointestinal (GI) cancer patients may not be considered for therapy with fluoropyrimidines (FPs) because of previous cardiovascular (CV) toxicity or preexisting risk factors; such patients may benefit from raltitrexed-based therapy.Patient, tumor, and treatment characteristics, as well as clinical outcomes of all consecutively treated patients with raltitrexed at the Royal Marsden Hospital between October 1998 and July 2011 were examined. GI cancer patients who developed CV toxicity as a result of FPs and those with significant CV risk factors receiving raltitrexed were included in this analysis.A total of 247 patients (155 and 92 with CV FP-related CV toxicities and significant CV risk factors, respectively) treated with raltitrexed alone or in combination were examined after a median follow-up of 47.1 months. CV toxicity profiles of patients receiving capecitabine (n = 110) and 5-fluorouracil (n = 45) were largely similar. Of raltitrexed-treated patients, 13 (5%) experienced CV toxicities and 1 ( 0.1%) died as a result of myocardial infarction. The median progression-free survival (PFS) and overall survival (OS) were 36.0 months (95% confidence interval [CI], 26.5-48.6) and 44.3 months (95% CI, 33.1-56.8), respectively. The 5-year survival for early stage GI malignancies (n = 140) was 62.0% (95% CI, 50.1-71.9). Median PFS and OS were not reached in this group (interquartile range = 38.4 months to NR); median PFS and OS for advanced GI malignancies (n = 107) were 18.8 (95% CI, 11.9-25.7) and 23.7 months (95% CI, 17.0-26.9), respectively.A raltitrexed-based regimen is well-tolerated therapy with comparable efficacy to FPs in patients with GI malignancies with significant CV toxicities or risk factors.

548 Background: RAS status in tissue and/or liquid biopsies and tumour location (sidedness) are predictive markers of patients’ response to anti-EGFR mABs. MiR-31-3p expression has been correlated with clinical benefit from anti-EGFR mABs with chemotherapy. We aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemo-refractory mCRC patients treated with single agent anti-EGFR mABs in the PROSPECT-C trial (NCT02994888). Methods: MiR-31-3p was tested by in-situ hybridization in 91 pre-treatment (PT) core biopsies from 45 mCRC patients. Sequential tissue biopsies obtained PT, at time of best response and at disease progression were tested to monitor changes in miR-31-3p expression over treatment. In 34 patients miR-31-3p, gender, sidedness, previous lines of treatment and RAS status in PT cell free (cf) DNA were evaluated in multivariate Cox and logistic regression models. Results: Patients with low miR-31-3p expression in PT biopsies showed better overall response rate (ORR: 58.3% vs 22.2%), median progression free survival (mPFS: 4.21 vs 2.27 months) and overall survival (mOS: 4.21 vs 2.27 mo) compared to those with high miR-31-3p expression (Hazard Ratio for PFS high vs low: 1.96; 95% CI: 0.98-3.88; p: 0.06 and HR for OS high vs low: 2.14; 95% CI: 1.04- 4.40; p: 0.04) adjusting for age, gender and sidedness. There was significant association between ORR and miR-31-3p expression (χ2 test p: 0.029). MiR-31-3p expression was an independent predictor of response, adjusting for gender, previous treatment lines and RAS (odds ratio: 0.14; 95% CI: 0.02-1.00, p: 0.048). A trend towards improved mPFS (5.10 vs 2.27 mo) and mOS (15.23 vs 4.67 mo) was noted in miR31-3p low vs high group in cfDNA RAS wild-type patients. No significant change in miR-31-3p expression were observed in archival tissue and sequential tissue biopsies. Conclusions: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mABs. Further studies are needed to test if miR-31-3p combined with cfDNA RAS test can identify best responders in specific clinical niches.

535 Background: The bispecific antibody CEA-TCB binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells. This triggers T cell killing of colorectal cancer cell lines expressing moderate to high levels of CEA at the cell surface (Bacac, Clin Cancer Res 2016). Patient derived organoids (PDOs) may more accurately represent patient tumors than established cell lines. Yet, determinants of CEA-TCB resistance have not been studied in PDOs. Methods: PDOs were established from biopsies of eight multidrug-resistant metastatic CRCs, GFP labelled and adapted to 2D culture. Allogenic CD8 T cells and CEA-TCB or a non-targeting control antibody were added and cancer cell killing and growth were monitored for 10 days. CEA expression of PDOs was determined by FACS. Results: CRC PDOs could be categorized into three groups based on CEA cell-surface expression: CEAhigh (n = 3), CEAlow (n = 2), and CEA heterogeneous PDOs (n = 3) that stably maintained populations of both CEAhigh and CEAlow cells, which has not previously been described in CRC cell lines. Heterogeneity of cell-surface CEA expression is common in CRC cells in patients, supporting that PDOs may better represent these tumors than established cell lines. CEAhigh cells were sensitive whereas CEAlow cells showed resistance to CEA-TCB. All PDOs with heterogeneous CEA expression were resistant to CEA-TCB, suggesting that CEA-negative cells maintain cancer cell growth. Culture of FACS sorted CEAhigh and CEAlow cells from PDOs with heterogeneous CEA expression demonstrated high plasticity of CEA expression which may contribute to rapid resistance acquisition through CEA antigen loss. Conclusions: These results suggest that cell-surface CEA expression is a major determinant of CEA-TCB sensitivity and resistance in PDOs. In addition, we identified heterogeneous CEA expression in several PDOs and demonstrated that this could confer CEA-TCB resistance in vitro. These PDO models are likely to provide insights into the mechanism of CEA loss and may inform therapeutic opportunities to counter CEA-TCB resistance. RNA-sequencing and functional experiments are ongoing to investigate this and will be presented.

Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.

Climate change due to anthropogenic greenhouse gases (GHG) is expected to have important impacts on water resources, with a variety of societal impacts. Recent research has shown that applying different methodologies to assess hydrologic impacts can lead to widely diverging projections of water resources. The authors classify methods of projecting hydrologic impacts of climate change into those that estimate potential evapotranspiration (PET) based on air temperature and those that estimate PET based on components of the surface energy budget. In general, air temperature–based methods more frequently show reductions in measures of water resources (e.g., water yield or soil moisture) and greater sensitivity than those using energy budget–based methods. There are significant trade-offs between these two methods in terms of ease of use, input data required, applicability to specific locales, and adherence to fundamental physical constraints: namely, conservation of energy at the surface. Issues of uncertainty in climate projections, stemming from imperfectly known future atmospheric GHG concentrations and disagreement in projections of the resultant climate, are compounded by questions of methodology and input data availability for models that connect climate change to accompanying changes in hydrology. In the joint atmospheric–hydrologic research community investigating climate change, methods need to be developed in which the energy and moisture budgets remain consistent when considering their interaction with both the atmosphere and water resources. This approach should yield better results for both atmospheric and hydrologic processes.

The present study examined the practice of forgiveness among participants from China (N = 172) and New Zealand (N = 91). We tested a theoretical model describing the relationships between collectivism, individualism, and forgiveness. Participants from China were more collectivistic and less individualistic than were participants from New Zealand. Overall, participants from New Zealand were more forgiving than were participants from China. Collectivism was positively related to decisional forgiveness in Chinese participants. Decisional forgiveness independently predicted conciliatory behaviour among participants from China, but this was not the case for participants from New Zealand. Thus, the hypothesized model received qualified support.

Isolated methylmalonic aciduria (MMA) results either from a defect in the mitochondrial enzyme methylmalonylCoA mutase (MCM), or in the intracellular conversion of vitamin B 12 (cobalamin) into its active coenzyme adenosylcobalamin (AdoCbl). Mutations in the MMAB gene affect the function of the enzyme ATP:cob(I)alamin adenosyltransferase (ATR) and the production of AdoCbl. Measurement of MCM function in cultured patient fibroblasts, followed by somatic cell complementation analysis in cases where MCM function is decreased, has classically been used to diagnose the cblB cobalamin disorder. A patient with persistent MMA, who could not be diagnosed using traditional somatic cell studies, was subsequently shown by sequencing in a clinical laboratory to contain two variants in the MMAB gene. This observation brings into question whether somatic cell studies have failed to diagnose other cblB patients with mild cellular phenotypes. A high resolution melting analysis (HRMA) assay was developed for the MMAB gene. It was used to scan 96 reference samples and two cohorts of patients: 42 patients diagnosed with cblB by complementation studies; and 181 patients with undiagnosed MMA. MMAB mutations, including one novel nonsense mutation (c.12 C>A [p.C4X]), were identified in all members of the cblB cohort. Four patients with undiagnosed MMA, including the index case described above, were found to contain variants in the MMAB gene: c.185C>T (p.T62M), c.394T>C (p.C132R), c.398C>T (p.S133F), c.521C>T (p.S174L), c.572G>A (p.R191Q). Only the index case was found to have two variants, suggesting that somatic cell studies diagnose almost all cblB patients.

Systems thinking and system dynamics simulation can provide insights for developing effective plans to protect the environmental integrity of natural systems impacted by human activities. In this study, a system archetype known as growth and underinvestment is hypothesized to explain the eutrophication problem of Lake Allegan in Michigan and identify policy leverage points for mitigation. An integrated system dynamics model is developed to simulate the interaction between key socioeconomic subsystems and natural processes driving eutrophication. The model is applied to holistically characterize the lake’s recovery from its hypereutrophic state and assess a number of proposed total maximum daily load (TMDL) reduction policies, including phosphorus load reductions from point sources and nonpoint sources. It is shown that for a TMDL plan to be effective, it should be considered a component of a continuous sustainability process, addressing the functionality of dynamic feedback relationships between s...

There is a longstanding concern about middle-class capture of the benefits of public service provision, although relatively little evidence exists on the exact nature of any advantage or on the processes by which this comes about. Using a framework developed from Gal (J. Gal, 1998. Formulating the Matthew Principle: on the role of the middle-classes in the welfare state. Scandinavian Journal of Social Welfare, 7, 42–55), and via two case studies of street cleansing services in the UK, the article explores the ways in which middle-class service users assert influence in relation to service design, resource allocation and practice on the ground. It explores how urban managers respond to middle-class influence, revealing the ways in which influence is accommodated and the benefits of this to middle-class service users. It also evidences how urban managers attempt to resist aspects of middle-class advantage, and the challenges such resistance presents. The article concludes that the need to ‘manage’ middle-cl...

We present a case of a patient with a rare case of atraumatic Mycobacterium avium-intracellulare complex lumbar osteomyelitis and epidural abscess with acute spinal cord compression. She presented to the emergency room with a 2-month history of progressive, bilateral hip and leg pain, with progression to an inability to ambulate. A magnetic resonance imaging of the lumbar spine revealed an epidural mass at L1 and associated compression of the conus medullaris. The patient was taken for decompression of the lumbar mass via a T12–L1 laminectomy. Approximately 6 weeks later, the final culture yielded M. avium-intracellulare complex epidural abscess. Mycobacterium avium-intracellulare complex–associated musculoskeletal infection is extremely rare, and to date, we have identified only 8 other cases in the literature. This case presentation will add to existing literature and highlight the continued need to consider atypical mycobacterial infection as a cause of unremitting back pain in immunocompromised individuals.

Background Since 1975 cells lines from patients with suspected inborn errors of vitamin B 12 metabolism have been referred to our laboratory because of elevations of homocysteine, methylmalonic acid, or both. Design Cultured fibroblasts from patients were subjected to a battery of tests: incorporation of labelled propionate and methyltetrahydrofolate into cellular macromolecules, to test the functional integrity of methylmalonyl-CoA mutase and methionine synthase, respectively; uptake of labelled cyanocobalamin and synthesis of adenosylcobalamin and methylcobalamin; and, where applicable, complementation analysis. Results This approach has allowed for the discovery of novel steps in the cellular transport and metabolism of vitamin B 12 , including those involving cellular uptake, the efflux of vitamin B 12 from lysosomes, and the synthesis of adenosylcobalamin and methylcobalamin. For all of these disorders, the responsible genes have been discovered. Conclusion The study of highly selected patients with suspected inborn errors of metabolism has consistently resulted in the discovery of previously unknown metabolic steps and has provided new lessons in biology.

The aim of this study is to assess the cross-cultural applicability of the Chinese version of the Inventory of School Motivation (ISM; McInerney & Sinclair, 1991) in the Hong Kong context using both within-network and between-network approaches to construct validation. The ISM measures four types of achievement goals: mastery, performance, social, and extrinsic goals. A total of 697 high school students participated in the study. Results of the within-network test showed that the ISM had good internal consistency reliability. Confirmatory factor analysis supported the hypothesized four-factor structure. In addition, multigroup confirmatory factor analyses showed factorial invariance across students of different genders, year levels, and school types. The between-network test indicated that the achievement goals assessed by the ISM correlated systematically with different aspects of students’ self-concepts. These findings provide evidence of the applicability of the ISM among Hong Kong Chinese students. Im...

The cblE disorder is an inherited disorder of vitamin B12 metabolism that results in elevated levels of homocysteine and decreased methionine in body fluids. Renal complications have been reported in patients with cblC disease, but not in those with cblE disease. The renal complications of cblC disease include thrombotic microangiopathy (TMA), neonatal hemolytic uremic syndrome, chronic renal failure, tubulointerstitial nephritis and proximal renal tubular acidosis. Previously, we reported a patient with cblC disease who had an atypical glomerulopathy that manifested with proteinuria and progressive renal insufficiency. Studies were done on cultured fibroblasts. Renal biopsy tissue was examined by light and electron microscopy. There was decreased incorporation of labeled methyltetrahydrofolate and decreased synthesis of methylcobalamin. Complementation analysis placed the patient into the cblE complementation group. The findings from the histological and ultrastructural studies of renal biopsy were similar, but not identical, to those of idiopathic membranoproliferative glomerulonephritis (MPGN) and overlapped with those of TMA. We describe a patient with cblE disease who had an atypical glomerulopathy similar to MPGN. Additional findings included migraine headaches, hypothyroidism and livedo reticularis.

Achievement goal theorists have mostly focused on the role of mastery and performance goals in the school setting with little attention being paid to social goals. The aim of this study was to explore the role of social goals in influencing educational outcomes in two collectivist cultures: Hong Kong and the Philippines. Results showed that social goals were able to predict additional variance in various adaptive educational outcomes even after controlling for the effects of mastery and performance goals. Implications for cross-cultural research are discussed.

Folate and vitamin B12 metabolism are essential for de novo purine synthesis, and several defects in these pathways have been associated with immunodeficiency. Here we describe the occurrence of severe combined immunodeficiency (SCID) with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities in which hydroxocobalamin and folate therapy provided partial immune reconstitution. Whole exome sequencing identified compound heterozygous mutations in the MTHFD1 gene, which encodes a trifunctional protein essential for processing of single-carbon folate derivatives. We now report the immunologic details of this novel genetic cause of SCID and the response to targeted metabolic supplementation therapies. This finding expands the known metabolic causes of SCID and presents an important diagnostic consideration given the positive impact of therapy.

To reproduce historical stream flows, climate and land-use change studies require watershed models with physically based parameters, rather than empirical models that are simply calibrated. With this in mind, soil moisture accounting and the temperature index (degree-day) snowmelt models embodied in the Hydrologic Engineering Center's hydrologic modeling system (HEC-HMS) are applied to three Great Lakes watersheds—Kalamazoo, Maumee, and St. Louis—with different climatic and land-use characteristics. Watershed and subwatershed models are calibrated and validated on a daily time step using gauge precipitation measurements, observed snow water equiv- alent data, and physically based parameters estimated using geospatial databases. Results are compared with area-scaled outputs from the National Oceanic and Atmospheric Administration (NOAA) large basin runoff model (LBRM) for historical conditions. The results show modest improvements resulting from the increased spatial resolution of the HEC-HMS models, in addition to the benefits of the more process- based snow algorithm in HEC-HMS, particularly for the snow-dominated St. Louis watershed. However, both LBRM and HEC-HMS models had difficulty reproducing peaks in late winter and early spring runoff, and discrepancies could not be attributed to any systematic errors in the snowmelt models. DOI: 10.1061/(ASCE)HE.1943-5584.0000591. © 2013 American Society of Civil Engineers. CE Database subject headings: Hydrologic models; Snow; Calibration; Runoff; Great Lakes; Watersheds. Author keywords: Hydrologic modeling; Snow modeling; Calibration; Hydrologic Engineering Center's hydrologic modeling system (HEC-HMS); Snow water equivalent; Large basin runoff model; Great Lakes; Runoff.

Derivatives of vitamin B12 (cobalamin) are essential cofactors for enzymes required in intermediary metabolism. Defects in cobalamin metabolism lead to disorders characterized by the accumulation of methylmalonic acid and/or homocysteine in blood and urine. The most common inborn error of cobalamin metabolism combined methylmalonic acidemia and hyperhomocysteinemia cblC type is caused by mutations in MMACHC. However several individuals with presumed cblC based on cellular and biochemical analysis do not have mutations in MMACHC. We used exome sequencing to identify the genetic basis of an X linked form of combined methylmalonic acidemia and hyperhomocysteinemia designated cblX. A missense mutation in a global transcriptional coregulator HCFC1 was identified in the index case. Additional male subjects were ascertained through two international diagnostic laboratories and 13/17 had one of five distinct missense mutations affecting three highly conserved amino acids within the HCFC1 kelch domain. A common phenotype of severe neurological symptoms including intractable epilepsy and profound neurocognitive impairment along with variable biochemical manifestations was observed in all affected subjects compared to individuals with early onset cblC. The severe reduction in MMACHC mRNA and protein within subject fibroblast lines suggested a role for HCFC1 in transcriptional regulation of MMACHC which was further supported by the identification of consensus HCFC1 binding sites in MMACHC. Furthermore siRNA mediated knockdown of HCFC1 expression resulted in the coordinate downregulation of MMACHC mRNA. This X linked disorder demonstrates a distinct disease mechanism by which transcriptional dysregulation leads to an inborn error of metabolism with a complex clinical phenotype. © 2013 The American Society of Human Genetics.