Building A Winning NFL Roster: Best Practices For Sustained Success

The purpose of this capstone is to identify and analyze the factors that contribute to team success in the National Football League through a review of relevant literature, a survey of league personnel, and firsthand experience as a football administrator. This project first studies quantitative data regarding player acquisition, specifically the data behind the NFL entry draft. Next, the current literature regarding off the field processes such as leadership, organizational culture and engagement were reviewed and finally, a two-step Delphi method survey was distributed to a panel of current league professionals. This paper aims to find the most efficient and effective way for teams to acquire players and several ways to optimize that talent based on the best practices researched in organizational culture and leadership

Conductance spectra of (Nb, Pb, In)/NbP -- superconductor/Weyl semimetal junctions

The possibility of inducing superconductivity in type-I Weyl semimetal through coupling its surface to a superconductor was investigated. A single crystal of NbP, grown by chemical vapor transport method, was carefully characterized by XRD, EDX, SEM, ARPES techniques and by electron transport measurements. The mobility spectrum of the carriers was determined. For the studies of interface transmission, the (001) surface of the crystal was covered by several hundred nm thick metallic layers of either Pb, or Nb, or In. DC current-voltage characteristics and AC differential conductance through the interfaces as a function of the DC bias were investigated. When the metals become superconducting, all three types of junctions show conductance increase, pointing out the Andreev reflection as a prevalent contribution to the subgap conductance. In the case of Pb-NbP and Nb-NbP junctions, the effect is satisfactorily described by modified Blonder-Tinkham-Klapwijk model. The absolute value of the conductance is much smaller than that for the bulk crystal, indicating that the transmission occurs through only a small part of the contact area. An opposite situation occurs in In-NbP junction, where the conductance at the peak reaches the bulk value indicating that almost whole contact area is transmitting and, additionally, a superconducting proximity phase is formed in the material. We interpret this as a result of indium diffusion into NbP, where the metal atoms penetrate the surface barrier and form very transparent superconductor-Weyl semimetal contact inside. However, further diffusion occurring already at room temperature leads to degradation of the effect, so it is observed only in the pristine structures. Despite of this, our observation directly demonstrates possibility of inducing superconductivity in a type-I Weyl semimetal.Comment: Accepted for Phys. Rev. B. 13 pages, 12 figures. Second version with major revisions. The title was changed. One author R. Jakiela added. New inset to Fig. 8(A). New fits in Fig. 8 (B) and Fig. 10 (B). Added figures 12 (C)-(E). Added Fig. 12 (F) with SIMS data. Rewritten chapters III-C-2 and III-C-3. Reference no. 38 removed, 11 new references: 9, 21, 22, 40-44, 46-49 were adde

Copy-Number Variants in Patients with a Strong Family History of Pancreatic Cancer

Copy-number variants such as germ-line deletions and amplifications are associated with inherited genetic disorders including familial cancer. The gene or genes responsible for the majority of familial clustering of pancreatic cancer have not been identified. We used representational oligonucleotide microarray analysis (ROMA) to characterize germ-line copy number variants in 60 cancer patients from 57 familial pancreatic cancer kindreds. Fifty-seven of the 60 patients had pancreatic cancer and three had nonpancreatic cancers (breast, ovary, ovary). A familial pancreatic cancer kindred was defined as a kindred in which at least two first-degree relatives have been diagnosed with pancreatic cancer. Copy-number variants identified in 607 individuals without pancreatic cancer were excluded from further analysis. A total of 56 unique genomic regions with copy-number variants not present in controls were identified, including 31 amplifications and 25 deletions. Two deleted regions were observed in two different patients, and one in three patients. The germ-line amplifications had a mean size of 662 Kb, a median size of 379 Kb (range 8.2 Kb to 2.5 Mb) and included 425 known genes. Examples of genes included in the germ-line amplifications include the MAFK, JunD and BIRC6 genes. The germ-line deletions had a mean size of 375Kb, a median size 151 Kb (range 0.4 Kb to 2.3 Mb) and included 81 known genes. In multivariate analysis controlling for region size, deletions were 90% less likely to involve a gene than were duplications (p < 0.01). Examples of genes included in the germ-line deletions include the FHIT, PDZRN3 and ANKRD3 genes. Selected deletions and amplifications were confirmed using real-time PCR, including a germ-line amplification on chromosome 19. These genetic copy-number variants define potential candidate loci for the familial pancreatic cancer gene

Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with &#60;5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC

Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification

Pancreatic cancer is one of the most lethal of all cancers. The median survival is 6 months, and less than 5% of those diagnosed survive 5-years. Recurrent genetic deletions and amplifications in 73 pancreatic adenocarcinomas, the largest sample set analyzed to date for pancreatic cancer, were defined using comparative genomic hybridization The recurrent genetic alterations identified target a number of previously well-characterized genes, as well as regions that contain possible new oncogenes and tumor suppressor genes. We have focused on chromosome 19q13, a region frequently found amplified in pancreatic cancer, and demonstrate how boundaries of common regions of mutation can be mapped, and how a gene, in this case PAK4 amplified on chromosome19q13, can be functionally validated. We show that although the PAK4 gene is not activated by mutation in cell lines with gene amplification, an oncogenic form of the KRAS2 gene is present in these cells, and oncogenic KRAS2 can activate PAK4. In fact in the three samples we identified with PAK4 gene amplification, the KRAS2 gene was activated and genomically amplified. The kinase activity of the PAK4 protein is significantly higher in cells with genomic amplification as compared to cells without amplification. Our study demonstrates the utility of analyzing copy number data in a large set of neoplasms to identify genes involved in cancer. We have generated a useful dataset which will be particularly useful for the pancreatic cancer community as efforts are undertaken to sequence the pancreatic cancer genome

Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis

Surveillance for pancreatic cancer in high-risk individuals

Background Surveillance of individuals at high risk of pancreatic ductal adenocarcinoma (PDAC) and its precursors might lead to better outcomes. The aim of this study was to determine the prevalence and outcomes of PDAC and high-risk neoplastic precursor lesions among such patients participating in surveillance programmes. Methods A multicentre study was conducted through the International CAncer of the Pancreas Screening (CAPS) Consortium Registry to identify high-risk individuals who had undergone pancreatic resection or progressed to advanced PDAC while under surveillance. High-risk neoplastic precursor lesions were defined as: pancreatic intraepithelial neoplasia (PanIN) 3, intraductal papillary mucinous neoplasia (IPMN) with high-grade dysplasia, and pancreatic neuroendocrine tumours at least 2 cm in diameter. Results Of 76 high-risk individuals identified in 11 surveillance programmes, 71 had undergone surgery and five had been diagnosed with inoperable PDAC. Of the 71 patients who underwent resection, 32 (45 per cent) had PDAC or a high-risk precursor (19 PDAC, 4 main-duct IPMN, 4 branch-duct IPMN, 5 PanIN-3); the other 39 patients had lesions thought to be associated with a lower risk of neoplastic progression. Age at least 65 years, female sex, carriage of a gene mutation and location of a lesion in the head/uncinate region were associated with high-risk precursor lesions or PDAC. The survival of high-risk individuals with low-risk neoplastic lesions did not differ from that in those with high-risk precursor lesions. Survival was worse among patients with PDAC. There was no surgery-related mortality. Conclusion A high proportion of high-risk individuals who had surgical resection for screening- or surveillance-detected pancreatic lesions had a high-risk neoplastic precursor lesion or PDAC at the time of surgery. Survival was better in high-risk individuals who had either low- or high-risk neoplastic precursor lesions compared with that in patients who developed PDAC

Precursor lesions of early onset pancreatic cancer

Early onset pancreatic cancer (EOPC) constitutes less than 5% of all newly diagnosed cases of pancreatic cancer (PC). Although histopathological characteristics of EOPC have been described, no detailed reports on precursor lesions of EOPC are available. In the present study, we aimed to describe histopathological picture of extratumoral parenchyma in 23 cases of EOPCs (definition based on the threshold value of 45 years of age) with particular emphasis on two types of precursor lesions of PC: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMNs). The types, grades, and densities of precursor lesions of PC were compared in patients with EOPCs, in young patients with neuroendocrine neoplasms (NENs), and in older (at the age of 46 or more) patients with PC. PanINs were found in 95.6% of cases of EOPCs. PanINs-3 were found in 39.1% of EOPC cases. Densities of all PanIN grades in EOPC cases were larger than in young patients with NENs. Density of PanINs-1A in EOPC cases was larger than in older patients with PC, but densities of PanINs of other grades were comparable. IPMN was found only in a single patient with EOPC but in 20% of older patients with PC. PanINs are the most prevalent precursor lesions of EOPC. IPMNs are rarely precursor lesions of EOPC. Relatively high density of low-grade PanINs-1 in extratumoral parenchyma of patients with EOPC may result from unknown multifocal genetic alterations in pancreatic tissue in patients with EOPCs

Serous cystic neoplasm of the pancreas: A multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas)

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58\u2005years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40\u2005mm (2-200)), 9% had resection beyond 1\u2005year of follow-up (3\u2005years (1-20), size at diagnosis: 25\u2005mm (4-140)) and 39% had no surgery (3.6\u2005years (1-23), 25.5\u2005mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1\u2005year (n=1271), size increased in 37% (growth rate: 4\u2005mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN

The reg4 Gene, Amplified in the Early Stages of Pancreatic Cancer Development, Is a Promising Therapeutic Target

BACKGROUND: The aim of our work was to identify the genes specifically altered in pancreatic adenocarcinoma and especially those that are altered early in cancer development. METHODOLOGY/PRINCIPAL FINDINGS: Gene copy number was systematically assessed with an ultra-high resolution CGH oligonucleotide microarray in DNA from samples of pancreatic cancer. Several new cancer-associated variations were observed. In this work we focused on one of them, involving the reg4 gene. Gene copy number gain of the reg4 gene was confirmed by qPCR in 14 cancer samples. It was also found with increased copy number in most PanIN3 samples. The relationship betweena gain in reg4 gene copy number and cancer development was investigated on the human pancreatic cancer cell line Mia-PaCa2 xenografted under the skin of nude mice. When cells were transfected with a vector allowing reg4 expression, they generated tumors almost twice larger in size. In addition, these tumors were more resistant to gemcitabine treatment than control tumors. Interestingly, weekly intraperitoneal administration of a monoclonal antibody to reg4 halved the size of tumors generated by Mia-PaCa2 cells, suggesting that the antibody interfered with a paracrine/autocrine mechanism involving reg4 and stimulating cancer progression. The addition of gemcitabine resulted in further reduction, tumors becoming 5 times smaller than control. Exposure to reg4 antibody resulted in a significant decrease in intra-tumor levels of pAkt, Bcl-xL, Bcl-2, survivin and cyclin D1. CONCLUSIONS/SIGNIFICANCE: It was concluded that adjuvant therapies targeting reg4 could improve the standard treatment of pancreatic cancer with gemcitabine