John H. Gibbon, Jr., M.D.: surgical innovator, pioneer, and inspiration.

Throughout history there have been many discoveries that have changed the world, including Albert Einstein’s theory of relativity, Alexander Graham Bell’s telephone, and Jack Kilby and Robert Noyce’s microchip. There are a few analogous contributions that have been made in medicine: Sir Alexander’s discovery of penicillin, Lister’s principles of antiseptic technique, Salk and Sabin’s vaccines for polio, as well as numerous others. These innovative thinkers all had two factors in common. First, they were pioneers who faced problems that had no solutions at the time and who refused to accept the status quo in the face of great scrutiny and resistance. Second, their contributions would forever change the world. In 1930, a profound experience with a patient would forever change Dr. John H. Gibbon, Jr. and stimulate an idea to create a device that at the time sounded audacious and impossible. His device would temporarily take the role of both the heart and lungs to make repairs inside the heart or the great vessels. Twentythree years later, Dr. Gibbon used his machine to perform the first successful bypass-assisted open heart surgery

2005 Revised Omaha Economic Development Plan: Plan for Northeast Omaha

The 2005 Revised OEDP provides OEDC with current data and analysis to initiate and complete a strategic process to develop an action plan for community and economic development activities and projects. The 2005 Revised Overall Economic Development Plan (OEDP) prepared by the Center for Public Affairs Research (CPAR) at the University of Nebraska at Omaha (UNO) for the Omaha Economic Development Corporation (OEDC) replaces the original OEDP first prepared in 1978. While a variety of revisions and updates over the years helped keep the original OEDP relatively current and helpful in development activities, in 2005 OEDC President Alvin Goodwin commissioned CPAR to provide a new basic planning document for the organization. Working with OEDC staff, and using the original OEDP as a framework, faculty and staff from CPAR, with the assistance of UNO graduate students, collected and analyzed data for the 2005 Revised Overall Economic Development Plan. The Revised OEDP retains and updates several of the sections from the original Plan but also adds new sections. Overall economic development plans contain a wealth of information about the demographic, social, and economic characteristics of the geographic area targeted for development by a community development corporation (CDC). CDCs, like the Omaha Economic Development Corporation, engage in many and varied community and economic development projects in its service area, and the overall economic development plan provides needed information to implement these projects. For example, the OEDP helps the community development corporation identify community needs as well as opportunities for business and economic development. Data from the OEDP can also be utilized for marketing and promotional purposes to attract new firms and customers. The OEDP serves as a source of information for formulating broad, long-term organizational goals, as well as specific, short-term development strategies and actions. Finally, the OEDP helps coordinate development activities, plans, and projects among the range of other organizations working in or adjacent to the target area

Promoter keyholes enable specific and persistent multi-gene expression programs in primary T cells without genome modification

Non-invasive epigenome editing is a promising strategy for engineering gene expression programs, yet potency, specificity, and persistence remain challenging. Here we show that effective epigenome editing is gated at single-base precision via 'keyhole' sites in endogenous regulatory DNA. Synthetic repressors targeting promoter keyholes can ablate gene expression in up to 99% of primary cells with single-gene specificity and can seamlessly repress multiple genes in combination. Transient exposure of primary T cells to keyhole repressors confers mitotically heritable silencing that persists to the limit of primary cultures in vitro and for at least 4 weeks in vivo, enabling manufacturing of cell products with enhanced therapeutic efficacy. DNA recognition and effector domains can be encoded as separate proteins that reassemble at keyhole sites and function with the same efficiency as single chain effectors, enabling gated control and rapid screening for novel functional domains that modulate endogenous gene expression patterns. Our results provide a powerful and exponentially flexible system for programming gene expression and therapeutic cell products

CCL3 and MMP-9 are induced by TL1A during death receptor 3 (TNFRSF25)-dependent osteoclast function and systemic bone loss

FLC was funded by an Arthritis Research UK PhD studentship (Grant code: 18598) awarded to ASW, ECYW and MDS. JOW was funded by a British Heart Foundation PhD studentship (Reference: FS/11/26/ 28750). ACB's PhD studentship was jointly funded by the School of Medicine and Rheumatology Research Fund (Cardiff University) and LJ's PhD studentship was jointly funded by the School of Medicine and the President's Scholarship Fund (Cardiff University) awarded to ASW. ECYW was additionally funded by MRC Project Grant G0901119.Peer reviewedPublisher PD

Impact of Obesity on Perioperative Morbidity and Mortality Following Pancreaticoduodenectomy

Background: Obesity has been implicated as a risk factor for perioperative and postoperative complications. The aim of this study was determine the impact of obesity on morbidity and mortality in patients undergoing pancreaticoduodenectomy (PD). Study Design: Between January 2000 and July 2007, 262 patients underwent PD at Thomas Jefferson University Hospital (TJUH), of whom 240 had complete data, including body mass index (BMI) for analysis. Data on BMI, preoperative parameters, operative details, and post-operative course were collected. Patients were categorized as obese (BMI \u3e30 kg/m2), overweight (25≤BMI\u3c30), or normal weight (BMI\u3c25). Complications were graded according to previous published scales. Other endpoints included length of postoperative hospital stay, blood loss, and operative duration. Analyses were performed using univariate and multivariable models. Results: There were 103 (42.9%) normal weight, 71 (29.6%) overweight and 66 (27.5%) obese patients. There were 5 perioperative deaths (2.1%) with no differences across BMI categories. A significant difference in median operative duration and blood loss between obese and normal weight patients was identified (439vs. 362.5minutes, p= 0.0004; 650 vs. 500 ml, p=0.0139). Furthermore, median length of stay was marginally significantly longer for by BMI (9.5 vs. 8 days, p=0.095). While there were no significant differences in superficial wound infections, obese patients did have an increased rate of serious complications compared to normal weight patients (24.2% vs. 13.6%, respectively; p=0.10). Conclusions: Obese patients undergoing PD have a significantly increased blood loss and longer operative time, but do not have a significantly increased length of postoperative hospital stay or rate of serious complications. These findings should be considered when assessing patients for operation and when counseling patients regarding operative risk, but do not preclude obese individuals from undergoing definitive pancreatic surgery

Splicing and the Evolution of Proteins in Mammals

It is often supposed that a protein's rate of evolution and its amino acid content are determined by the function and anatomy of the protein. Here we examine an alternative possibility, namely that the requirement to specify in the unprocessed RNA, in the vicinity of intron–exon boundaries, information necessary for removal of introns (e.g., exonic splice enhancers) affects both amino acid usage and rates of protein evolution. We find that the majority of amino acids show skewed usage near intron–exon boundaries, and that differences in the trends for the 2-fold and 4-fold blocks of both arginine and leucine show this to be owing to effects mediated at the nucleotide level. More specifically, there is a robust relationship between the extent to which an amino acid is preferred/avoided near boundaries and its enrichment/paucity in splice enhancers. As might then be expected, the rate of evolution is lowest near intron–exon boundaries, at least in part owing to splice enhancers, such that domains flanking intron–exon junctions evolve on average at under half the rate of exon centres from the same gene. In contrast, the rate of evolution of intronless retrogenes is highest near the domains where intron–exon junctions previously resided. The proportion of sequence near intron–exon boundaries is one of the stronger predictors of a protein's rate of evolution in mammals yet described. We conclude that after intron insertion selection favours modification of amino acid content near intron–exon junctions, so as to enable efficient intron removal, these changes then being subject to strong purifying selection even if nonoptimal for protein function. Thus there exists a strong force operating on protein evolution in mammals that is not explained directly in terms of the biology of the protein

Pancreatic Ductal Adenocarcinoma: Long-Term Survival Does Not Equal Cure

Background: Pancreatic ductal adenocarcinoma represents 90% of pancreatic cancers and is an important cause of cancer death in the United States. Operative resection remains as the only treatment providing prolonged survival, but even after a curative resection, 5-year survival rates are low. Our aim was to identify the prognostic factors for long-term survival after resection of pancreatic ductal adenocarcinoma related to patients, treatments, and tumor biology. Methods: Retrospective review identified 959 patients who underwent resection of their pancreatic adenocarcinoma between February 1985 and December 2010, of whom 499 were resected before November 2006 and represent the cohort we describe in this study. Patient, tumor, and treatment-related variables were assessed for their associations with 5- and 10-year overall survival. Results: Of the 499 patients, 49% were female and median age was 65 years. The majority of patients had stage IIb disease (60%). Actual 5-year survival after resection of pancreatic adenocarcinoma was 19% (95/499), and actual 10-year survival was 10% (33/329). Significant clinicopathologic factors predicting 5- and 10-year survival were negative margins and negative nodal status. Interestingly, 41% (39/95) of long-term survivors had positive nodes and 24% (23/95) had positive margins. Conclusion: Pancreatic ductal adenocarcinoma demonstrates a very heterogeneous biology, but patients with negative resection margins and node negative cancers are more likely to survive 5 years after resection. However, our series demonstrates that the biology of the cancer rather than simple pathologic factors determine a patient's prognosis

How the merger of two white dwarfs depends on their mass ratio: orbital stability and detonations at contact

Despite their unique astrophysical relevance, the outcome of white dwarf binary mergers has so far only been studied for a very restricted number of systems. Here we present the results of a survey with more than two hundred simulations systematically scanning the white dwarf binary parameter space. We consider white dwarf masses ranging from 0.2 to 1.2 $M_\odot$ and account for their different chemical compositions. We find excellent agreement with the orbital evolution predicted by mass transfer stability analysis. Much of our effort in this paper is dedicated to determining which binary systems are prone to a thermonuclear explosion just prior to merger or at surface contact. We find that a large fraction of He-accreting binary systems explode: all dynamically unstable systems with accretor masses below 1.1 $M_\odot$ and donor masses above $\sim$ 0.4 $M_\odot$ are found to trigger a helium detonation at surface contact. A substantial fraction of these systems could explode at earlier times via detonations induced by instabilities in the accretion stream, as we have demonstrated in our previous work. We do not find definitive evidence for an explosion prior to merger or at surface contact in any of the studied double carbon-oxygen systems. Although we cannot exclude their occurrence if some helium is present, the available parameter space for a successful detonation in a white dwarf binary of pure carbon-oxygen composition is small. We demonstrate that a wide variety of dynamically unstable systems are viable type Ia candidates. The next decade thus holds enormous promise for the study of these events, in particular with the advent of wide-field synoptic surveys allowing a detailed characterization of their explosive properties.Comment: 13 pages, 10 figures, submitted to MNRA

Unravelling the ORFan Puzzle

ORFans are open reading frames (ORFs) with no detectable sequence similarity to any other sequence in the databases. Each newly sequenced genome contains a significant number of ORFans. Therefore, ORFans entail interesting evolutionary puzzles. However, little can be learned about them using bioinformatics tools, and their study seems to have been underemphasized. Here we present some of the questions that the existence of so many ORFans have raised and review some of the studies aimed at understanding ORFans, their functions and their origins. These works have demonstrated that ORFans are an untapped source of research, requiring further computational and experimental studies