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Funding Acknowledgements Type of funding sources: None. Background The Global Registry of Acute Coronary Events (GRACE) risk score is widely recommended for risk assessment in patients with acute coronary syndrome (ACS). The Charlson Comorbidity Index (CCI) is a recognized measure of comorbid burden, and a useful tool for estimating prognosis in patients with multiple coexisting illnesses. Despite it has been validated in the context of ACS-related mortality, scarce and conflicting data still exist about the role of the CCI when added to the traditional GRACE risk score for outcome prediction in patients with acute coronary syndrome (ACS). Purpose The assessment of the potential predictive value of the CCI both for short, and long term all-cause mortality, in a contemporary ACS population, and its potential adding value beyond the GRACE risk score. Methods All consecutive admission due to ST-elevation myocardial infarction-STEMI, non ST elevated myocardial infarction-NSTEMI, and unstable angina-UA, from 01/01/2018 to 31/12/2020 were retrospectively reviewed from an internal database of a tertiary cardiac center in Italy. Logistic and Cox proportional regression analysis were performed in order to assess the contribution of the CCI on short and long term mortality. In order to specify the CCI adding value to the GRACE score, several measures of improvement in discrimination (increase in the area under the receiver-operating characteristic curve-AUC, the integrated discrimination improvement-IDI, and the continuous net reclassification improvement-cNRI>0) , were implemented. Robustness of the results were assessed through an internal validation procedure with bootstrapping. Results A total of 1310 patients (646 STEMI, 588 NSTEMI, and 76 UA) were identified. Almost 28% were female, and the median age was 68 (58-78). 97 (7,4%) and 136 (11,2%) deaths occurred, respectively, in hospital and during long term follow-up (median follow-up time: 12 months; IQR: 8-23). After multivariate logistic regression analysis the CCI was not associated with in-hospital death, while it was significantly and independently associated with the long-term mortality along with GRACE score (HR: 1,33, 95% CI: 1,22-1,43; p0: 0.678, p < 0.001, Table 1) and integrated discrimination improvement (IDI: 0.08, p < 0.001). Conclusion The CCI is a predictor of long-term mortality and improves risk stratification of patients with ACS over the GRACE risk score.

Key minerals, including zircon, apatite, titanite, rutile, monazite, xenotime, allanite and garnet, can retain critical information about petrogenetic and geodynamic processes. This Special Publication showcases snapshots of the latest developments using key minerals in igneous, metamorphic and detrital rocks through current-state reviews, contributions focused on case studies and newly developed techniques.

Background There is a positive continuous association between Lipoprotein(a) (Lp[a]) levels and the risk of recurrent ischemic events in patients with recent myocardial infarction (MI). However, the prognostic significance of the association between high Lp(a) levels and diabetes has been poorly investigated after MI. Purpose The aim of this study was to evaluate the association of Lp(a) levels with the long-term risk of adverse events in post-MI patients, and to investigate whether diabetes may influence this association. Methods Consecutive MI patients who underwent urgent/emergent coronary angiography at our Institution from February 2013 to June 2019 were prospectively collected. Lp(a) serum concentrations was expressed for increasing range values (≤10, >10–30, >30–50, >50–70, and ≥70 mg/dL). The primary outcome was the recurrence of MI; the secondary outcome was all-cause death. The propensity score weighting technique was used to account for potential confounding between patients with and without diabetes. Results The study population consisted of 1018 post-MI patients (median age: 63 years; 76% males). Diabetes was reported in 280 patients (27.5%). The median value of Lp(a) was 10 mg/dL, and patients with diabetes showed significantly lower Lp(a) levels than patients without diabetes (p=0.025). At a median follow-up of 1121 days, the primary outcome was reported in 109 patients (10.7%), and the secondary outcome in 100 (9.8%). After propensity score weighting, there was a significant association between increasing Lp(a) range values and the primary outcome both in the overall population (p trend = 0.030) and in non-diabetic patients (p trend = 0.009), but not in diabetics. Conversely, no significant association with the risk of all-cause mortality across increasing Lp(a) categories both in the overall population and in the study groups according to the presence or not of diabetes was found. Compared with the lowest Lp(a) category, Lp(a) plasma levels >70 mg/dL were independently associated with the risk of recurrent MI (HR: 3.222; 95% CI, 1.225–8.478, p=0.018) and all-cause death (HR: 2.656; 95% CI, 1.009–6.991, p=0.048) in non-diabetic patients, but not in diabetics. Conclusions In this real-world post-MI population, Lp(a) serum levels were lower in diabetic than in non-diabetic patients. Increasing Lp(a) levels were significantly associated with the risk of recurrent MI, and very high Lp(a) serum concentration (>70 mg/dL) independently predicted recurrent MI and death in non-diabetic patients, but not in diabetics. These results reinforce the importance of routine assessment of Lp(a) levels after MI, particularly in patients without diabetes. Funding Acknowledgement Type of funding sources: None.

Aims To describe the baseline clinical, laboratory and angiographic characteristics of patients with acute myocardial infarction (MI) according to the presence or not of diabetes mellitus (DM), and to evaluate if DM may influence the effect of lipoprotein(a) [Lp(a)] serum level on long–term outcome in this very high–risk population. Methods This was a retrospective, single–center, study including consecutive patients admitted with MI diagnosis between January 1, 2017, and December 31, 2020. The availability of data on baseline Lp(a) serum level was considered as an inclusion criterion. The study population was divided into two groups according to the presence or not of DM. The Lp(a) value of 50 mg/dL was used to test the hypothesis of a different effect of Lp(a) on the clinical outcome of patients with or without DM. The primary study outcome was all–cause death at 3–year follow–up. Results The study population included 997 patients (mean age 63.7±13.5 years; 75.7% were males). Diabetes was reported in 280 (28.1%) patients. DM patients were older than those without DM (67.8±12.1 vs. 62.0±13.7 years, p Conclusion In this MI population, Lp(a) was independently associated with long–term mortality in patients without DM, but not in patients with DM. Whether DM can modify the effect of Lp(a) on clinical outcome after MI requires confirmation by larger prospective studies.

Endothelial cells adopt tissue-specific characteristics to instruct organ development and regeneration1,2. This adaptability is lost in cultured adult endothelial cells, which do not vascularize tissues in an organotypic manner. Here, we show that transient reactivation of the embryonic-restricted ETS variant transcription factor 2 (ETV2)3 in mature human endothelial cells cultured in a serum-free three-dimensional matrix composed of a mixture of laminin, entactin and type-IV collagen (LEC matrix) ‘resets’ these endothelial cells to adaptable, vasculogenic cells, which form perfusable and plastic vascular plexi. Through chromatin remodelling, ETV2 induces tubulogenic pathways, including the activation of RAP1, which promotes the formation of durable lumens4,5. In three-dimensional matrices—which do not have the constraints of bioprinted scaffolds—the ‘reset’ vascular endothelial cells (R-VECs) self-assemble into stable, multilayered and branching vascular networks within scalable microfluidic chambers, which are capable of transporting human blood. In vivo, R-VECs implanted subcutaneously in mice self-organize into durable pericyte-coated vessels that functionally anastomose to the host circulation and exhibit long-lasting patterning, with no evidence of malformations or angiomas. R-VECs directly interact with cells within three-dimensional co-cultured organoids, removing the need for the restrictive synthetic semipermeable membranes that are required for organ-on-chip systems, therefore providing a physiological platform for vascularization, which we call ‘Organ-On-VascularNet’. R-VECs enable perfusion of glucose-responsive insulin-secreting human pancreatic islets, vascularize decellularized rat intestines and arborize healthy or cancerous human colon organoids. Using single-cell RNA sequencing and epigenetic profiling, we demonstrate that R-VECs establish an adaptive vascular niche that differentially adjusts and conforms to organoids and tumoroids in a tissue-specific manner. Our Organ-On-VascularNet model will permit metabolic, immunological and physiochemical studies and screens to decipher the crosstalk between organotypic endothelial cells and parenchymal cells for identification of determinants of endothelial cell heterogeneity, and could lead to advances in therapeutic organ repair and tumour targeting., The transient reactivation of ETV2 in adult human endothelial cells reprograms these cells to become adaptable vasculogenic endothelia that in three-dimensional matrices self-assemble into vascular networks that can transport blood and physiologically arborize organoids and decellularized tissues.

Background Although interest in frailty has expanded among cardiology experts over the past 2 decades, its integration, as part of cardiovascular disease management, is still lacking, above all in the acute cardiac care setting. The Clinical Frailty Scale (CFS) is a brief guided tool to assess frailty in hospital settings without specialist equipment. Purpose Our objective was to test the performance of the CFS in an older, unselected population, admitted to an Intensive Cardiac Care Unit (ICCU) during the year 2019. Methods The study sample included 431 patients ≥65 years old, admitted to an ICCU of a tertiary cardiac center in Italy. The CFS ranged from “very fit: 1” to “terminally ill: 9”, but it was considered present at a score ≥5. Our primary endpoint was defined by a combination of severe complications requiring critical care and in-hospital death. The data were collected from the hospital discharge summary and the electronic chart records. Results 158 patients (36.7%) were frail. These individuals had greater comorbidity and higher in-hospital mortality (Table 1). After a multivariable logistic regression analysis, 4 predictors were identified: signs of congestive heart failure (OR: 8.51, 95% Confidence Interval-CI: 4.63–14.6; p Conclusions The CFS is a simple guided frailty tool that may enhance outcome prediction in the acute cardiac care setting. These findings merit evaluation in larger cohorts of unselected patients. Funding Acknowledgement Type of funding sources: None.

In utero transplantation (IUT) of hematopoietic stem cells (HSC) has been proposed as a strategy for the prenatal treatment of congenital hematological diseases. However, levels of long-term hematopoietic engraftment achieved in experimental IUT to date are sub-therapeutic, likely due to host fetal HSC out-competing their bone-marrow (BM) derived donor equivalents for space in the hematopoietic compartment. In the present study we demonstrate that amniotic fluid stem cells (AFSC; c-Kit+/Lin-) have hematopoietic characteristics and, thanks to their fetal origin, favourable proliferation kinetics in vitro and in vivo, which are maintained when the cells are expanded. IUT of autologous/congenic freshly-isolated or cultured AFSC resulted in stable mutli-lineage hematopoietic engraftment, far higher to that achieved with BM-HSC. Intravascular IUT of allogenic AFSC was not successful as recently reported after intraperitoneal IUT. Herein we demonstrated that this likely due to a failure of timely homing of donor cells to the host fetal thymus resulted in lack of tolerance induction and rejection. This study reveals that intravascular IUT leads to a remarkable hematopoietic engraftment of AFSC in the setting of autologous/congenic IUT, and confirms the requirement for induction of central tolerance for allogenic IUT to be successful. Autologous, gene engineered and in-vitro expanded AFSC could be used as a stem cell/gene therapy platform for the in utero treatment of inherited disorders of hematopoiesis. SIGNIFICANCE STATEMENT: Amniotic fluid stem cells can be expanded without losing their hematopoietic characteristics In utero transplantation of allogenic AFSC results in adaptive immune response and donor cell rejection, due to failure of timely homing of donor cells to the host fetal thymus and lack of central tolerance induction. Autologous/congenic amniotic fluid stem cells can be transplanted in utero and result in stable, multi-lineage, long-term hematopoietic engraftment that is significantly higher to that achieved with bone marrow-derived cells and could be therapeutic in many inherited disorders of hematopoiesis. © AlphaMed Press 2019.

Background: In late 2012, Hurricane Sandy struck the eastern United States. Healthcare infrastructure in New York City—including long-term care facilities (LTCFs)—was affected significantly. The authors examined the impact of the storm on LTCFs 2 years after the event, using a qualitative approach consisting of a semistructured interview focused on preparedness and response. Important insights regarding preparedness and response may be lost by quantitative analysis or outcome measurement alone. During Sandy, individuals at LTCFs experienced the event in important subjective ways that, in aggregate, could lead to valuable insights about how facilities might mitigate future risks. The authors used data from a semistructured interview to generate hypotheses regarding the preparation and response of LTCFs. The interview tool was designed to help develop theories to explain why LTCF staff and administrators experienced the event in the way they did, and to use that data to inform future policy and research. Methods: Representatives from LTCFs located in a heavily affected area of New York City were approached for participation in a semistructured interview. Interviews were digitally recorded and transcribed. Recurrent themes were coded based on time period (before, during, or after the storm) and content. A grounded theory approach was used to identify important themes related to the participants’ experiences.Results: A total of 21 interviews were conducted. Several overarching themes were identified, including a perception that facilities had not prepared for an event of such magnitude, of inefficient communication and logistics during evacuation, and of lack of easily identifiable or appropriate resources after the event. Access to electrical power emerged as a key identifier of recovery for most facilities. The experience had a substantial psychological impact on LTCF staff regardless of whether they evacuated or sheltered in place during the storm.Conclusion: Representatives from LTCFs affected by Sandy experienced the preparation, response, and recovery phases of the event with a unique perspective. Their insights offer evidence which can be used to generate testable hypothesis regarding similar events in the future, and can inform policy makers and facility administrators alike as they prepare for extreme weather events in similar settings. Results specifically suggest that LTCFs develop plans which carefully address the unique qualities of extreme weather events, including communication with local officials, evacuation and transfer needs in geographic areas with multiple facilities, and plans for the safe transfer of residents. Emergency managers at LTCFs should consider electrical power needs with the understanding that in extreme weather events, power failures can be more protracted than in other types of emergencies.

Background The relevance of laparoscopic resection of intrahepatic cholangiocarcinoma (ICC) remains debated. The aim of this study was to compare laparoscopic (LLR) and open (OLR) liver resection for ICC, with specific focus on textbook outcome and lymph node dissection (LND). Methods Patients undergoing LLR or OLR for ICC were included from two French, nationwide hepatopancreatobiliary surveys undertaken between 2000 and 2017. Patients with negative margins, and without transfusion, severe complications, prolonged hospital stay, readmission or death were considered to have a textbook outcome. Patients who achieved both a textbook outcome and LND were deemed to have an adjusted textbook outcome. OLR and LLR were compared after propensity score matching. Results In total, 548 patients with ICC (127 LLR, 421 OLR) were included. Textbook-outcome and LND completion rates were 22.1 and 48.2 per cent respectively. LLR was independently associated with a decreased rate of LND (odds ratio 0.37, 95 per cent c.i. 0.20 to 0.69). After matching, 109 patients remained in each group. LLR was associated with a decreased rate of transfusion (7.3 versus 21.1 per cent; P = 0.001) and shorter hospital stay (median 7 versus 14 days; P = 0.001), but lower rate of LND (33.9 versus 73.4 per cent; P = 0.001). Patients who underwent LLR had lower rate of adjusted TO completion than patients who had OLR (6.5 versus 17.4 per cent; P = 0.012). Conclusion The laparoscopic approach did not substantially improve quality of care of patients with resectable ICC.

Background & Aims Herein, we aimed to establish benchmark values – based on a composite indicator of healthcare quality – for the performance of laparoscopic left lateral sectionectomy (LLLS) and laparoscopic right hepatectomy (LRH) using data from expert centers. Methods Data from a nationwide multicenter survey including all patients undergoing LLLS and LRH between 2000 and 2017 were analyzed. Textbook outcome (TO) completion was considered in patients fulfilling all 6 of the following characteristics: negative margins, no transfusion, no complication, no prolonged hospital stay, no readmission and no mortality. For each procedure, a cut-off laparoscopic liver resection (LLR) volume by center was associated with TO on multivariable analysis. These cut-offs defined the expert centers. The benchmark values were set at the 75th percentile of median outcomes among these expert centers. Results Among 4,400 LLRs performed in 29 centers, 855 patients who underwent LLLS and 488 who underwent LRH were identified. The overall incidences of TO after LLLS and LRH were 43.7% and 23.8%, respectively. LLR volume cut-offs of 25 LLR/year (odds ratio [OR] 2.45; bootstrap 95% CI 1.65–3.69; p = 0.001) and 35 LLR/year (OR 2.55; bootstrap 95% CI 1.34–5.63; p = 0.003) were independently associated with completion of TO after LLLS and LRH, respectively. Eight centers for LLLS and 6 centers for LRH, including 516 and 346 patients undergoing LLLS/LRH respectively, reached these cut-offs and were identified as expert centers. After LLLS, benchmark values of severe complication, mortality and TO completion were defined as ≤5.3%, ≤1.2% and ≥46.6%, respectively. After LRH, benchmark values of severe complication, mortality and TO completion were ≤20.4%, ≤2.8% and ≥24.2%, respectively. Conclusions This study provides an up-to-date reference on the benchmark performance of LLLS and LRH in expert centers. Lay summary In a nationwide French survey of laparoscopic liver resection, expert centers were defined according to the completion of a textbook outcome, which is a composite indicator of healthcare quality. Benchmark values regarding intra-operative details and outcomes were established using data from 516 patients with laparoscopic left lateral sectionectiomy and 346 patients with laparoscopic right hepatectomy from expert centers. These values should be used as a reference point to improve the quality of laparoscopic resections.

The aim was to analyse the impact of cirrhosis on short-term outcomes after laparoscopic liver resection (LLR) in a multicentre national cohort study.This retrospective study included all patients undergoing LLR in 27 centres between 2000 and 2017. Cirrhosis was defined as F4 fibrosis on pathological examination. Short-term outcomes of patients with and without liver cirrhosis were compared after propensity score matching by centre volume, demographic and tumour characteristics, and extent of resection.Among 3150 patients included, LLR was performed in 774 patients with (24·6 per cent) and 2376 (75·4 per cent) without cirrhosis. Severe complication and mortality rates in patients with cirrhosis were 10·6 and 2·6 per cent respectively. Posthepatectomy liver failure (PHLF) developed in 3·6 per cent of patients with cirrhosis and was the major cause of death (11 of 20 patients). After matching, patients with cirrhosis tended to have higher rates of severe complications (odds ratio (OR) 1·74, 95 per cent c.i. 0·92 to 3·41; P = 0·096) and PHLF (OR 7·13, 0·91 to 323·10; P = 0·068) than those without cirrhosis. They also had a higher risk of death (OR 5·13, 1·08 to 48·61; P = 0·039). Rates of cardiorespiratory complications (P = 0·338), bile leakage (P = 0·286) and reoperation (P = 0·352) were similar in the two groups. Patients with cirrhosis had a longer hospital stay than those without (11 versus 8 days; P = 0·018). Centre expertise was an independent protective factor against PHLF in patients with cirrhosis (OR 0·33, 0·14 to 0·76; P = 0·010).Underlying cirrhosis remains an independent risk factor for impaired outcomes in patients undergoing LLR, even in expert centres.El objetivo de este estudio fue analizar el impacto de la cirrosis en los resultados a corto plazo después de la resección hepática laparoscópica (laparoscopic liver resection, LLR) en un estudio de cohortes multicéntrico nacional. MÉTODOS: Este estudio retrospectivo incluyó todos los pacientes sometidos a LLR en 27 centros entre 2000 y 2017. La cirrosis se definió como fibrosis F4 en el examen histopatológico. Los resultados a corto plazo de los pacientes con hígado cirrótico (cirrhotic liver CL) (pacientes CL) y los pacientes con hígado no cirrótico (non-cirrhotic liver, NCL) (pacientes NCL) se compararon después de realizar un emparejamiento por puntaje de propension del volumen del centro, las características demográficas y del tumor, y la extensión de la resección.Del total de 3.150 pacientes incluidos, se realizó LLR en 774 (24,6%) pacientes CL y en 2.376 (75,4%) pacientes NCL. Las tasas de complicaciones graves y mortalidad en el grupo de pacientes CL fueron del 10,6% y 2,6%, respectivamente. La insuficiencia hepática posterior a la hepatectomía (post-hepatectomy liver failure, PHLF) fue la principal causa de mortalidad (55% de los casos) y se produjo en el 3,6% de los casos en pacientes CL. Después del emparejamiento, los pacientes CL tendieron a tener tasas más altas de complicaciones graves (razón de oportunidades, odds ratio, OR 1,74; i.c. del 95% 0,92-0,41; P = 0,096) y de PHLF (OR 7,13; i.c. del 95% 0,91-323,10; P = 0,068) en comparación con los pacientes NCL. Los pacientes CL estuvieron expuestos a un mayor riesgo de mortalidad (OR 5,13; i.c. del 95% 1,08-48,6; P = 0,039) en comparación con los pacientes NCL. Los pacientes CL presentaron tasas similares de complicaciones cardiorrespiratorias graves (P = 0,338), de fuga biliar (P = 0,286) y de reintervenciones (P = 0,352) que los pacientes NCL. Los pacientes CL tuvieron una estancia hospitalaria más larga (11 versus 8 días; P = 0,018) que los pacientes NCL. La experiencia del centro fue un factor protector independiente de PHLF (OR 0,33; i.c. del 95% 0,14-0,76; P = 0,010) pacientes CL. CONCLUSIÓN: La presencia de cirrosis subyacente sigue siendo un factor de riesgo independiente de peores resultados en pacientes sometidos a resección hepática laparoscópica, incluso en centros con experiencia.

Cancer cells require increased levels of NADPH for increased nucleotide synthesis and for protection from ROS. Recent studies show that increased NADPH is generated in several ways. Activated AKT phosphorylates NAD kinase (NADK), increasing its activity. NADP formed, is rapidly converted to NADPH by glucose 6-phosphate dehydrogenase and malic enzymes, overexpressed in tumor cells with mutant p53. Calmodulin, overexpressed in some cancers, also increases NADK activity. Also, in IDH1/2 mutant cancer, NADPH serves as the cofactor to generate D-2 hydroxyglutarate, an oncometabolite. The requirement of cancer cells for elevated levels of NADPH provides an opportunity to target its synthesis for cancer treatment.

Heralded among America's master watercolorists, Winslow Homer (1836–1910) explored a wide range of themes, styles and techniques in the approximately 685 watercolors he painted from 1873–1905. This chapter discusses 59 watercolors from the collections of The Art Institute of Chicago and the National Gallery of Art, Washington DC, which encompass Homer's three decades of watercolor painting. A comprehensive scientific study of the palette of these works—carried out mostly using non-invasive techniques—serves as the basis for an extensive interdisciplinary discussion on the importance of color, texture and transparency in the artist's oeuvre. Homer reached a pinnacle in his career with his sophisticated representations of a changing natural landscape. His artistic sensibility was married to a mastery of the watercolor technique, which is illustrated by the increasing technical complexity and sophisticated exploitation of individual pigment properties in his works. This survey provides new material for the art historians studying Homer's complex watercolor technique. It offers insight into the importance of the artist's deliberate choices of colorants and their juxtapositions in his work. A deep knowledge of the chronological evolution of the artist's materials and painting techniques also offers valuable guidance to conservators charged with preserving these prized and admired watercolors.

Intestinal failure (IF), following extensive anatomical or functional loss of small intestine (SI), has debilitating long-term effects on infants and children with this condition. Priority of care is to increase the child’s length of functional intestine, jejunum in particular, to improve nutritional independence. Here we report a robust protocol for reconstruction of autologous intestinal mucosal grafts using primary IF patient materials. Human jejunal intestinal organoids derived from paediatric IF patients can be expanded efficiently in vitro with region-specific markers preserved after long-term culture. Decellularized human intestinal matrix with intact ultrastructure is used as biological scaffolds. Proteomic and Raman spectroscopic analyses reveal highly analogous biochemical composition of decellularized human SI and colon matrix, implying that they can both be utilised as scaffolds for jejunal graft reconstruction. Indeed, seeding of primary human jejunal organoids to either SI or colonic scaffolds in vitro can efficiently reconstruct functional jejunal grafts with persistent disaccharidase activity as early as 4 days after seeding, which can further survive and mature after transplantation in vivo. Our findings pave the way towards regenerative medicine for IF patients.

Intestinal failure, following extensive anatomical or functional loss of small intestine, has debilitating long-term consequences for children1. The priority of patient care is to increase the length of functional intestine, particularly the jejunum, to promote nutritional independence2. Here we construct autologous jejunal mucosal grafts using biomaterials from pediatric patients and show that patient-derived organoids can be expanded efficiently in vitro. In parallel, we generate decellularized human intestinal matrix with intact nanotopography, which forms biological scaffolds. Proteomic and Raman spectroscopy analyses reveal highly analogous biochemical profiles of human small intestine and colon scaffolds, indicating that they can be used interchangeably as platforms for intestinal engineering. Indeed, seeding of jejunal organoids onto either type of scaffold reliably reconstructs grafts that exhibit several aspects of physiological jejunal function and that survive to form luminal structures after transplantation into the kidney capsule or subcutaneous pockets of mice for up to 2 weeks. Our findings provide proof-of-concept data for engineering patient-specific jejunal grafts for children with intestinal failure, ultimately aiding in the restoration of nutritional autonomy.

Liver transplantation remains the treatment of choice for patients with end-stage liver disease. However, allograft availability continues to be a problem, and extending the criteria for organ acceptance is key. Deceased donors after electrical accidents, as well as electricity-traumatized allografts, are not common but should be considered suitable. This study describes 2 cases of heart-beating organ donors with electrical injury to the liver. In 1 case, the electric shock was the cause of death; in the second case, the injury was caused by defibrillation at organ procurement. Both allografts had sustained sizeable electrical injury, and both resulted in excellent early posttransplant outcomes. These cases demonstrate that electrocution is not a contraindication to donation and that electricity-traumatized allografts may remain transplantable after careful assessment. Education of all staff in the management of such donors can optimize utility of such allografts.

Purpose To investigate the effectiveness of a combination of 6-thioguanine (6-TG) and pralatrexate (PDX) in methylthioadenosine phosphorylase (MTAP)-deficient T-cell acute lymphoblastic leukemia (T-cell ALL). Methods CCRF-CEM (MTAP−/−) and Molt4 (MTAP+/+) T-cell ALL cell lines were treated with 6-TG or PDX and evaluated for efficacy 72 h later. NOD/SCID gamma mice bearing CEM or Molt4 xenografts were treated with 6-TG and PDX alone or in combination to evaluate antitumor effects. Results CEM cells were more sensitive to 6-TG and PDX in vitro than Molt4. In vivo, CEM cells were very sensitive to PDX and 6-TG, whereas Molt4 cells were highly resistant to 6-TG. A well-tolerated combination of PDX and 6-TG achieved significant tumor regression in CEM xenografts. Conclusions The loss of MTAP expression may be therapeutically exploited in T-cell ALL. The combination of 6-TG and PDX, with the inclusion of leucovorin rescue, allows for a safe and effective regimen in MTAP-deficient T-cell ALL.

Liver transplantation remains the treatment of choice for patients with end-stage liver disease. However, allograft availability continues to be a problem, and extending the criteria for organ acceptance is key. Deceased donors after electrical accidents, as well as electricity-traumatized allografts, are not common but should be considered suitable. This study describes 2 cases of heart-beating organ donors with electrical injury to the liver. In 1 case, the electric shock was the cause of death; in the second case, the injury was caused by defibrillation at organ procurement. Both allografts had sustained sizeable electrical injury, and both resulted in excellent early posttransplant outcomes. These cases demonstrate that electrocution is not a contraindication to donation and that electricity-traumatized allografts may remain transplantable after careful assessment. Education of all staff in the management of such donors can optimize utility of such allografts.

NAD+ kinase (NADK) catalyzes the phosphorylation of nicotinamide adenine dinucleotide (NAD+) to nicotinamide adenine dinucleotide phosphate (NADP+) using ATP as the phosphate donor. NADP+ is then reduced to NADPH by dehydrogenases, in particular glucose-6-phosphate dehydrogenase and the malic enzymes. NADPH functions as an important cofactor in a variety of metabolic and biosynthetic pathways. The demand for NADPH is particularly high in proliferating cancer cells, where it acts as a cofactor for the synthesis of nucleotides, proteins, and fatty acids. Moreover, NADPH is essential for the neutralization of the dangerously high levels of reactive oxygen species (ROS) generated by increased metabolic activity. Given its key role in metabolism and regulation of ROS, it is not surprising that several recent studies, including in vitro and in vivo assays of tumor growth and querying of patient samples, have identified NADK as a potential therapeutic target for the treatment of cancer. In this review, we will discuss the experimental evidence justifying further exploration of NADK as a clinically relevant drug target and describe our studies with a lead compound, thionicotinamide, an NADK inhibitor prodrug. Clin Cancer Res; 22(21); 5189–95. ©2016 AACR.

Dihydrofolate reductase (DHFR), because of its essential role in DNA synthesis, has been targeted for the treatment of a wide variety of human diseases, including cancer, autoimmune diseases, and infectious diseases. Methotrexate (MTX), a tight binding inhibitor of DHFR, is one of the most widely used drugs in cancer treatment and is especially effective in the treatment of acute lymphocytic leukemia, non-Hodgkin’s lymphoma, and osteosarcoma. Limitations to its use in cancer include natural resistance and acquired resistance due to decreased cellular uptake and decreased retention due to impaired polyglutamylate formation and toxicity at higher doses. Here, we describe a novel mechanism to induce DHFR degradation through cofactor depletion in neoplastic cells by inhibition of NAD kinase, the only enzyme responsible for generating NADP, which is rapidly converted to NADPH by dehydrogenases/reductases. We identified an inhibitor of NAD kinase, thionicotinamide adenine dinucleotide phosphate (NADPS), which led to accelerated degradation of DHFR and to inhibition of cancer cell growth. Of importance, combination treatment of NADPS with MTX displayed significant synergy in a metastatic colon cancer cell line and was effective in a MTX-transport resistant leukemic cell line. We suggest that NAD kinase is a valid target for further inhibitor development for cancer treatment.

The purpose of the present work was to investigate the in vivo concentrations of sorbic acid and vanillin as markers of the fate of organic acids (OA) and natural identical flavors (NIF) from a microencapsulated mixture and from the same mixture non-microencapsulated, and the possible consequences on the intestinal microbial fermentation. Fifteen weaned pigs were selected from 3 dietary groups and were slaughtered at 29.5 +/- 0.27 kg of BW. Diets were (1) control; (2) control supplemented with a blend of OA and NIF microencapsulated with hydrogenated vegetable lipids (protected blend, PB); and (3) control supplemented with the same blend of OA and NIF mixed with the same protective matrix in powdered form but without the active ingredient coating (non-protected blend, NPB). Stomach, cranial jejunum, caudal jejunum, ileum, cecum, and colon were sampled to determine the concentrations of sorbic acid and vanillin contained in the blend and used as tracers. Sorbic acid and vanillin were not detectable in pigs fed the control, and their concentrations were not different in the stomach of PB and NPB treatments. Pigs fed PB showed a gradual decrease of the tracer concentrations along the intestinal tract, whereas pigs fed NPB showed a decline of tracer concentration in the cranial jejunum and onwards, compared with the stomach concentrations. Sorbic acid and vanillin concentrations along the intestinal tract were greater (P = 0.02) in pigs fed PB compared with pigs fed NPB. Pigs fed PB had lower (P = 0.03) coliforms in the caudal jejunum and the cecum than pigs fed the control or NPB. Pigs fed the control or PB had a greater (P = 0.03) lactic acid bacteria plate count in the cecum than pigs fed NPB, which showed a reduction (P = 0.02) of lactic acid concentrations and greater (P = 0.02) pH values in the caudal jejunum. The protective lipid matrix used for microencapsulation of the OA and NIF blend allowed slow-release of both active ingredients and prevented the immediate disappearance of such compounds upon exiting the stomach.

Summary Background Effects of frequent nocturnal symptoms of gastro-oesophageal reflux disease (GERD-FNS) on health-related quality of life (HRQOL) and work productivity are not well documented. Aim To assess symptom severity, production loss, and HRQOL among employed adults with and without GERD-FNS. Methods Using several validated outcome measures in a web survey design, GERD was pre-specified as GERD Symptom and Medication Questionnaire score >9, and ≥1 episode of heartburn or acid regurgitation during the preceding week. GERD-FNS patients were those reporting ≥2 symptom-nights during the previous week; their outcomes were compared with those of patients having minimal or no nocturnal symptoms (GERD-NNS) and vs. non-GERD controls. Results Data were collected from 1002 GERD patients (476 GERD-FNS, 526 GERD-NNS) and 513 controls. Severe symptoms were more common, sleep abnormalities were more frequent (P

Rapidly proliferating tumors attempt to meet the demands for nucleotide biosynthesis by up-regulating folate pathways that provide the building blocks for pyrimidine and purine biosynthesis. Reduced folates are carriers of one carbon units required for the synthesis of purines, thymidylate and methionine, derived from serine, glycine and formate. As folate metabolism plays a key role in cell proliferation, the folate-requiring enzymes dihydrofolate reductase and thymidylate synthase have long been key targets for treatment of cancer. Recent studies show that the mitochondrial folate enzymes are also critical, in that they enable mitochondria to produce additional one carbon units for purine synthesis to allow for rapid growth. In transformed cells, methylene tetrahydrofolate dehydrogenase MTHFD2 is often reactivated and expressed along with other members of the serine synthesis, one carbon (folate) metabolism and glycine cleavage system, allowing for enhanced production of purines, ATP and NADPH, fueling cell proliferation [1]. More recently, it has been recognized that these enzymes are critical for the generation of NADH/NADPH, necessary for protection from ROS and required for macromolecular synthesis. MTHFD2 is a bifunctional enzyme with methylene dehydrogenase and cyclohydrolase activity that produces N-10 formyl tetrahydrofolate, the source of C2 and C8 in purines and NADH from methylenetetrahydrofolate and NAD [2]. The cytoplasmic enzyme, MTHFD1 uses NADP as a cofactor as compared to MTHFD2, which carries out the same enzyme activity using NAD, Mg++ and PO4-. In rapidly growing cancer cells, but not normal proliferating cells, MTHFD2 is the major source of formate for purine synthesis (Figure ​(Figure11). Figure 1 The cytoplasmic enzyme, MTHFD1, uses NADP as a cofactor as compared to MTHFD2, which carries out the same enzyme activity using NAD, Mg++ and PO4-. R= p-aminobenzoylglutamate Using gene expression arrays, we have shown that overexpression of mitochondrial enzymes, particularly MTHFD2, is associated with both high proliferation rates and cMYC overexpression [3]; this key role for MTHFD2 in cancer cell proliferation has recently been confirmed [4]. Most importantly, overexpression of MTHFD2 has been shown to be associated with poor prognosis of patients with breast cancer [5] and with an increased rate of invasion and metastasis [6]. That MTHFD2: 1) is over expressed in rapidly replicating tumor cells but not in adult tissue, and 2) enhances tumor cell proliferation provides a strong rationale for targeting this enzyme for selective cancer treatment [7]. The New Twist. It has recently been shown that MTHFD2 can have an impact on proliferation independent of its enzymatic activity [8]. In these studies, MTHFD2 was found in the nucleus, and co-localized with DNA replication sites. How this interaction enhances proliferation is unknown. That MTHFD2 has a dual effect on tumor cell proliferation, i.e., enhancing nucleotide synthesis directly and possibly “moonlighting” as a DNA binding protein [8] makes it an even more important and selective target for cancer treatment, but suggests that inhibition of enzyme activity alone may not be sufficient to effect tumor regression. If inhibition of this enzyme activity proves to be not effective, new approaches targeting transcription or translation may be required to achieve anti-tumor activity.

Introduction Postoperative delirium can be a serious consequence of major surgery, associated with longer hospital stays, readmission, cognitive and functional deterioration and mortality. Delirium is an acute, reversible disorder characterised by fluctuating course, inattention, disorganised thinking and altered level of consciousness. Delirium occurring in the hours immediately following anaesthesia and delirium occurring in the postoperative period of 1–5 days have been described as distinct clinical entities. This protocol describes an observational study with the aim of determining if delirium in the first hour following tracheal tube removal is a predictor of delirium in the 5 subsequent postoperative days. Improved understanding regarding the development of postoperative delirium would improve patient care and allow more effective implementation of delirium prevention measures. Methods and analysis Patients enrolled to the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomised controlled trial will be eligible for this substudy. A validated delirium assessment method, the 3-min Diagnostic Confusion Assessment Method and the Richmond Agitation and Sedation Scale will be used to assess 100 patients for delirium at 30 min and 60 min following tracheal tube removal. Patients will also be assessed for delirium over postoperative days 1–5 using three validated methods, the Confusion Assessment Method (CAM), CAM for the Intensive Care Unit and structured chart review. Logistic regression analysis will then be performed to test whether immediately postoperative delirium independently predicts subsequent postoperative delirium. Ethics and dissemination This observational substudy of ENGAGES has been approved by the ethics board of Washington University School of Medicine. Enrolment began in June 2016 and will continue until June 2017. Dissemination plans include presentations at scientific conferences and scientific publications. Trial registration number NCT02241655.

NAD(+) kinase (NADK) is the only known cytosolic enzyme that converts NAD(+) to NADP(+), which is subsequently reduced to NADPH. The demand for NADPH in cancer cells is elevated as reducing equivalents are required for the high levels of nucleotide, protein, and fatty acid synthesis found in proliferating cells as well as for neutralizing high levels of reactive oxygen species (ROS). We determined whether inhibition of NADK activity is a valid anticancer strategy alone and in combination with chemotherapeutic drugs known to induce ROS. In vitro and in vivo inhibition of NADK with either small-hairpin RNA or thionicotinamide inhibited proliferation. Thionicotinamide enhanced the ROS produced by several chemotherapeutic drugs and produced synergistic cell kill. NADK inhibitors alone or in combination with drugs that increase ROS-mediated stress may represent an efficacious antitumor combination and should be explored further.

We report an unusual case of an isolated, large, thrombosed hypogastric artery aneurysm presenting as a voluminous pelvic mass with bilateral hydroureteronephrosis. The patient underwent successful surgical removal of the mass. Histology confirmed an aneurysm of the left hypogastric artery.

The mixing behavior of b-octylglucoside and sodium decylsulfate in aqueous solution has been studied by various experimental techniques. The critical aggregation concentration (c.m.c.) of surfactants' mixtures has been determined by surface tension measurements. The results adapt reasonably well to the regular solution model, a favorable interaction between the two surfactants being found. The aggregation number of surfactants' mixtures, obtained by fluorescence quenching measurements, varies almost regularly between those of the two surfactants. Furthermore measurements of the Electronic Paramagnetic Resonance (EPR), employing the cationic molecule TEMPO-choline as spin probe, allowed the investigation of the hydrophobicity and surfactants' packing in the mixed micelles.

6Boehnnger Mannheim, Italv Summary Background: Early clinical trials have suggested that glutathione (GSH) offers protection from the toxic effects of cisplatin. Patients and methods: One hundred fifty-one patients with ovarian cancer (stage I-IV) were evaluated in a clinical trial of cisplatin (CDDP) ± glutathione (GSH). The objective was to determine whether GSH would enhance the feasibility of giving six cycles of CDDP at 100 mg/m2 without dose reduction due to toxicity. Results: When considering the proportion of patients receiving six courses of CDDP at any dose, GSH produced a significant advantage over control - 58% versus 39%, (P = 0.04). For these patients there was a significant difference between the reduction in creatinine clearance for GSH treated patients compared with control - 74% versus 62% (P = 0.006). Quality of life scores demonstrated that for patients receiving GSH there was a statistically significant improvement in depression, emesis, peripheral neurotoxicity, hair loss, shortness of breath and difficulty concentrating. As an indication of overall activity, these patients were statistically significantly more able to undertake housekeeping and shopping. Clinically assessed response to treatment demonstrated a trend towards a better outcome in the GSH group (73% versus 62%) but this was not statistically significant (P = 0.25). Conclusions: The results demonstrate that adding GSH to CDDP allows more cycles of CDDP treatment to be administered because less toxicity is observed and the patient's quality of life is improved.

Introduction Human hematopoietic stem cell transplantation (HSCT) has been used to treat a range of hematological and immunological disorders. As a result, the demand for hematopoietic stem cells (HSC) in clinical applications is increasing. Amniotic fluid stem cells (AFSC) serve as a potential alternative cell source for therapy. Amniotic fluid can be derived by amniocentesis or therapeutic amniodrainage. AFSC are multi-potent, have low risk of tumorigenicity, can be expanded and do not have legal or ethical limitations. The significant hematopoietic activity of murine AFSC led us to explore the potential of human AFSC (CD117/c-Kit+) towards hematopoietic differentiation and to reconstitution in vivo. Methods Human AFSC (2nd and 3rd trimester) and cord blood HSC (CB-HSC; control) were selected for CD117 and CD34 respectively using a MoFlo XDP sorter. Sorted cells (104 in 200μl PBS) were injected intravenously into sub-lethally irradiated NOD-SCID/IL2rγnull (NSG) mice (n=6/group). Hematopoietic engraftment of human cells (% of human CD45+ within total CD45+) and multi-lineage reconstitution (myeloid: CD13, CD14, CD15 and lymphoid: CD3, CD4 and CD8) were assessed at 16 weeks in blood, bone marrow (BM) and spleen by flow cytometry. For subsequent secondary transplants, BM mononuclear cells (MNC) derived from BM harvested from primary recipients of mice were intravenously injected into secondary recipients (1.5x107 MNC in 200μl PBS). Hematopoietic engraftment was assessed at 16 weeks post-transplantation (n=6/group). For further analysis of human donor cell engraftment, Q-PCR was performed on spleen samples harvested from primary and secondary recipients using oligonucleotide primers specific for human ALU repeat sequences; Immunohistochemistry was carried out using anti-human CD45 antibody and detected with a commercially available kit (Dako EnVision Plus, Dako). Results are expressed as mean±SEM, and statistical analysis was performed using 1-way ANOVA with Bonferroni post-hoc tests. Results Human AFSC engrafted the hematopoietic system of NSG mice at levels similar to the ones achieved with CB-HSC (blood: AFSC 7.5±1.3% vs. CB-HSC 6.1±2.2%, p=0.6; BM: AFSC 46.3±7.9% vs. CB-HSC 38.3±8.2%, p=0.6; spleen: AFSC 39.6±9.3% vs. CB-HSC 34.7±10.5%, p=0.7). Similarly, at 16 weeks following secondary transplantation, human donor cell engraftment was comparable between groups in blood (AFSC 11.5 ± 3.9% vs. CB-HSC 16.9 ± 3.9%, p=0.3) and other hematopoietic tissues. Q-PCR and immunohistochemistry confirmed donor cell engraftment in AFSC and CB-HSC groups. Importantly, there were no differences between groups in multi-lineage differentiation at 16 weeks post primary and secondary transplantation. Conclusion Human CD117/c-Kit+ AFSC have functional, multi-lineage hematopoietic potential that is similar to the current "gold-standard" stem cell source for hematopoietic transplantation. The ease of isolation during early gestation, as well as their gene-engineering and expansion potential make human AFSC a novel autologous fetal cell source for pre- and post-natal therapy of inherited hematological disorders. Disclosures No relevant conflicts of interest to declare.

Previous studies have documented the roles of transport via the reduced folate carrier, retention via polyglutamylation, and increased levels of the target enzyme, dihydrofolate reductase in sensitivity to methotrexate. Recent studies have shown that the mitochondrial enzymes in the cellular metabolism of serine, folate, and glycine are overexpressed in a subset of human cancers and that their expression is required for tumor maintenance. In this Perspective article, we propose that the expression of mitochondrial enzymes in the metabolism of serine and glycine, in addition to those involved in folate metabolism, are determinants of the response to methotrexate. Furthermore, we show that myc activation in tumors is associated with upregulation of these enzymes. We propose that patients whose tumors show this phenotype will be sensitive to folate antagonists targeting thymidylate or purine biosynthesis. Cancer Res; 73(2); 478–82. ©2012 AACR.

Introduction Castleman's disease (CD) is a rare benign disorder that may grow in any area where lymphoid tissue is normally present but the most frequent site is mediastinum (67%); the abdomen is rarely affected by this pathology. In the pathogenesis of CD an important role could be played by HHV-8. Diagnosis is difficult and the diagnostic certainty is obtained only by histological examination. For this disease there is no gold-standard treatment. Case report We report the case of a woman of 33 years of age affected by a rare form of abdominal nodal localization of Castleman's Disease for which the patient underwent surgery. Conclusion CD must be included in the differential diagnosis of retroperitoneal tumors even though the definitive diagnosis can only be achieved by histological and immunohistochemical examination. In the case of single location, the treatment of choice is surgical removal.

A low-IF very compact low power quadrature receiver for ZigBee applications is presented. The receiver saves area and power with a quadrature self oscillating mixer based on high Q bond-wire inductors. The prototype, integrated in CMOS 90 nm, provides 76 dB of maximum voltage gain, with a 10 dB noise figure, an IIP3 of -13 dBm and a phase noise of -124 dBc/Hz @ 3.5 MHz with an active area of only 0.23 mm2 and a power consumption of 3.6 mW (including the baseband complex filter).

In the design of a single chip for wireless-sensor-network and WPAN applications (e.g., IEEE 802.15.4), the receiver sensitivity is generally sacrificed in favor of a vanishing power consumption and a low-cost solution. There is a trade off between these two requirements, as the use of resonant loads offers high power efficiency while an inductor-free approach saves die area resulting in a cheaper design. Since an LC-oscillator topology is mandatory to achieve a minimal current draw, the reduction of the number of coils has to be done in the LNA, the mixer and the quadrature generator. In this work, starting from the LNA-Mixer and VCO (LMV) cell topology, a single-coil low-power receiver shares the bias current among all the RF blocks of the analog front-end. The receiver prototype chip consumes 3.6mW and has an active die area of 0.35mm2. It is based on a low-IF architecture and includes a baseband variable-gain complex filter for channel selection.

Effects of frequent nocturnal symptoms of gastro-oesophageal reflux disease (GERD-FNS) on health-related quality of life (HRQOL) and work productivity are not well documented.To assess symptom severity, production loss, and HRQOL among employed adults with and without GERD-FNS.Using several validated outcome measures in a web survey design, GERD was pre-specified as GERD Symptom and Medication Questionnaire score9, andor =1 episode of heartburn or acid regurgitation during the preceding week. GERD-FNS patients were those reportingor =2 symptom-nights during the previous week; their outcomes were compared with those of patients having minimal or no nocturnal symptoms (GERD-NNS) and vs. non-GERD controls.Data were collected from 1002 GERD patients (476 GERD-FNS, 526 GERD-NNS) and 513 controls. Severe symptoms were more common, sleep abnormalities were more frequent (P0.0001) and SF-36 scores lower (P0.05, all scores) among GERD-FNS patients vs. GERD-NNS patients. GERD-related work loss was greater among those with GERD-FNS vs. GERD-NNS (P0.0001). Work loss and functional limitations were more pronounced when comparing GERD-FNS cases vs. non-GERD controls.Employed adults with frequent nocturnal GERD report more severe symptoms, and are associated with impaired sleep, HRQOL and work productivity compared with controls and patients with minimal or no nocturnal symptoms.

Next generation sequencing (NGS) technologies are rapidly being incorporated into the clinic to facilitate decisions on cancer patient care. However, successful translation of NGS data requires knowledge on which DNA aberrations represent actionable events, either for development or re-positioning of approved agents to target their activated pathways. Recognizing this, large-scale tumor profiling efforts by consortia such as The Cancer Genome Atlas (TCGA) are cataloging genomic aberrations across major cancer lineages. These efforts have revealed an extraordinary level of genome complexity made up of not only key “driver” events critical to pathogenesis, but also numerous biologically-neutral “passengers” that accompany unstable tumor genomes. The challenge now is to find ways to identify functional driver aberrations, as targeting such events or their activated pathways has great potential for improving patient outcomes. To do this, we have developed high-throughput approaches to construct molecularly-barcoded versions of gene aberrations for functional screens. Specifically, we developed technologies that include (1) high-throughput, accurate modeling of somatic DNA mutations (somatic missense mutations and small insertions/deletions) using our robotics-driven platform of >35,000 sequenced-verified open reading frame (ORF) clones, (2) a molecular barcoding strategy that permits rapid DNA tagging of wild-type and mutant ORFs, (3) multi-fragment recombineering methodologies allowing construction of cancer fusion genes, and (4) combining the use of these reagents for individual or pooled functional screens in vitro and in vivo using human and mouse systems. We are using these technologies, which are widely applicable to all cancer types, to identify the highest priority targets to enroll in deep mechanistic studies and drug discovery programs. We have scaled our pipelines to functionalize thousands of cancer gene aberrations. Importantly, we are now constructing entire somatically-mutated exomes from individual patients sequenced in the clinic. As an example of our “Personalized Functionalization” approach, we screened individual pancreatic ductal adenocarcinoma (PDAC) patient-derived aberration libraries for mutations capable of promoting tumorigenesis in vivo using a mouse xenograft model engineered with regulatable KRASG12D, an oncogene active in the majority of PDAC patient tumors. These studies revealed potent aberration drivers that are active as individual drivers as well as those that are contextual and are only active in the presence of KRASG12D. Based on these results, we have chosen NAD Kinase (NADK) for deep mechanistic studies and drug discovery programs. NADK catalyzes the conversion of cytoplasmic NAD+ to NADP+/NADPH and thus aids other modes of cellular NADPH production. Our validation studies indicate that the NADK mutation results in robust gain-of-function kinase activity leading to its hyper-phosphorylation of NAD+ accompanied by reduced accumulation or reactive oxygen species and increased tumor formation and growth. Interestingly, recent work by others report other mechanisms by which KRAS rewires PDAC tumors to maximize energy production and promote NADPH accumulation to maintain redox state and tumor growth. Even though NADK is mutated at low frequency in PDAC, its selection demonstrates that the discovery of rare, functional aberrations may intersect or otherwise lead us to important pathways and potential therapeutic liabilities. Our ultimate goal is to functionally annotate thousands of somatic aberrations in cancer, the vast majority of which have not been previously recognized or assayed for clinical relevance. These systems will reveal high priority edited targets to enroll in deep mechanistic biology studies, drug discovery and development programs ultimately leading to personalized treatment strategies. Citation Format: Kenneth Scott, Yiu Huen Tsang, Turgut Dogruluk, Philip Tedeschi, Joseph Bertino, Gordon Mills. Functional prioritization of rare gene aberration drivers of cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr PR06.