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There are little published data on the transition of care in EB. We conducted a survey study recruiting EB patients from the Dystrophic EB Research Association (debra) website and centers caring for high numbers of EB patients in the United States and internationally from Sept 17, 2019 to Nov 3, 2021. The majority of participants had not discussed the transition of care with their healthcare providers, nor the healthcare needs to be required as an adult. Ongoing pediatric subspecialty care was reported by 12% of adults, most commonly in pediatric dermatology. Identified barriers to transition included the perceived lack of adult providers' knowledge about EB patient healthcare needs. The results suggest the need for transition guidelines, early discussions with families about transition, and practical information for the adult providers accepting care.

The purpose of this study was to examine how family involvement affects the environmental innovation of firms. While prior studies have shown that family involvement can enhance environmental performance, these environmental performances have been portrayed as firm activities to prevent environmental issues, such as air pollution, CO2 emissions, etc. We maintain that environmental performance should be more proactive and enable firms to transform their activities more fundamentally towards environmental protection. In this sense, we consider environmental innovation, i.e., technological development to address environmental issues, as a proactive measure enacting firm activities to address environmental issues. Furthermore, we determine whether and how family involvement can motivate firms to develop technologies for environmental performance. To illuminate this relation, we utilized a socioemotional wealth perspective, which provides useful insights into how family-controlled firms behave differently in comparison to non-family firms. Building on this socioemotional wealth approach, we suggest that family involvement helps firms engage in environmental innovation. In this study, we also explore how the positive link between family involvement and environmental innovation is dependent on family interlocks—the circumstance wherein a firm’s family directors are affiliated with the boards of directors of other firms. Specifically, we suggest that an increase in a firm’s family interlocks would strengthen the positive relationship between family involvement and environmental innovation. To test our ideas, we used a sample of 623 US public firms ranging from 1996 to 2010, which yielded 5047 firm-year observations. We find that family involvement facilitates the environmental innovation of firms. We also find that family interlocks intensify the positive effect of family involvement on environmental innovation. Finally, we discuss the theoretical and empirical implications of our results.

From the social exchange theory, this study examines the relationship between psychological contract breach, organizational cynicism, and union commitment, as well as the interaction effect of perceived union dual identity on the relationship between organizational cynicism and union commitment. We argue that contract breach has a positive impact on union commitment, and this relationship is mediated by organizational cynicism. Moreover, we suggest that the perceived union dual identity moderates the relationship between the two. To examine this, we sampled 371 employees of Chinese non-state-owned firms in 2019. The results show that, in the Chinese context, the psychological contract breach has a positive impact on organizational cynicism and union commitment. This relationship is weaker when the perceived union identity (state-oriented) is higher; it is stronger when the perceived union identity (labor-oriented) is higher.

This paper analyzes the selection processes behind post-schooling transitions into college enrollment, military service, long-term unemployment, and incarceration relative to civilian employment, examining to what extent these processes are racialized. Rather than analyzing a complete set of alternatives, previous research typically focuses on a limited set of these alternatives at a time, and rarely accounts for incarceration or long-term unemployment. Using individual-level panel data on the first post-high school transition from the National Longitudinal Survey of Youth 1997 Cohort, results show that white men experience positive transitions (college enrollment and military service) at higher rates and for longer periods than black men, who experience negative transitions (long-term unemployment and incarceration) at higher rates for longer periods than whites. Competing risk Cox regression analyses reveal that blacks’ transitions are polarized, showing that blacks in the upper distributions of standardized test scores and socioeconomic status are more likely to pursue a college education relative to their white counterparts, whereas blacks in the bottom of the standardized test score and socioeconomic status distribution are more likely to experience negative transitions than whites. Unlike prior research finding that military service provided “bridging careers” for racial minorities, black men are no longer more likely to join the military than whites. Instead, blacks now face a much higher risk of incarceration. Implications for intra-generational mobility and changing opportunity structures for racial minorities are discussed.

Recent clinical trials utilizing Interferon-alpha (IFN) in combination with chemoradiation have demonstrated significant improvements in the survival of patients with pancreatic cancer. However, efficacy was limited by the systemic toxicity of IFN and low intratumoral levels of the cytokine. We sought to address these drawbacks by using an Oncolytic Adenovirus expressing IFN (OAd-hamIFN) in combination with chemotherapy and/or radiation in regimens mimicking the IFN-based therapies used in clinical trials. IFN expressed from OAd-hamIFN potentiated the cytotoxicity of radiation and chemotherapy (5-FU, Gemcitabine, and Cisplatin), and enhanced pancreatic cancer cell death in both in vitro and in vivo experimental settings. Notably, synergism was demonstrated in therapeutic groups that combined the interferon-expressing oncolytic virus with chemotherapy and radiation. In an in vivo immunocompetent hamster model, treatment regimens combining oncolytic virus therapy with 5-FU and radiation demonstrated significant tumor growth inhibition and enhanced survival. This is the first study to report synergism between an IFN-expressing oncolytic adenovirus and chemoradiation-based therapies. When combined with an IFN-expressing OAd, there is a significant enhancement of radiation and especially chemoradiation, which may broaden the application of this new therapeutic approach to the pancreatic cancer patients who cannot tolerate existing chemotherapy regimens.

Aims/Introduction We sought to determine the association between change in fasting plasma glucose (FPG) and levels of liver enzymes, such as aspartate transaminase, alanine transaminase and gamma-glutamyltransferase, from health examinations. Materials and Methods A total of 9,393 health screen examinees with no evidence of viral hepatitis, liver diseases, abnormal liver function and diabetes in their past disease history were enrolled in the present study. All the participants underwent three health examinations. Group 1 and 4 were stationary groups of those with normal liver enzyme levels in the first and second health examinations (G1), and abnormal liver enzyme levels in the first and second health check-up (G4). Groups 2 and 3 were altered groups of those with abnormal liver enzyme levels in the first health examination, which became normal in the second health examination (G2), and from a normal liver enzymes level to an abnormal liver enzymes level (G3). Results FPG levels were elevated in male participants (P

Background Oncolytic adenoviruses provide a promising alternative for cancer treatment. Recently, adjuvant interferon (IFN)-alfa has shown significant survival benefits for pancreatic cancer, yet was impeded by systemic toxicity. To circumvent these problems adenovirus with high-level targeted IFN-alfa expression can be generated. Methods Conditionally replicative adenoviruses (CRAds) with improved virulence and selectivity for pancreatic cancer were generated. The vectors were tested in vitro, in vivo, and in human pancreatic cancer and normal tissue specimens. Results Adenoviral death protein and fiber modifications significantly improved oncolysis. CRAds selectively replicated in vitro, in vivo and showed persistent spread in cancer xenografts. They showed high-level replication in human pancreatic cancer specimens, but not in normal tissues. Improved IFN-CRAd oncolytic efficiency was shown. Conclusions Optimized cyclooxygenase-2 CRAds show highly favorable effects in vitro and in vivo. We report a pancreatic cancer–specific, highly virulent, IFN-expressing CRAd, and we believe that adenovirus-based IFN therapy offers a new treatment opportunity for pancreatic cancer patients.

Background Combination therapy with interferon alpha (IFN) is correlated with improved survival in patients with pancreatic ductal adenocarcinoma (PDAc) but frequently presents side effects. We designed a novel targeted adenovirus with replication restricted to cyclooxygenase 2 (Cox2)-overexpressing PDAcs and hypothesize that the locally delivered therapeutic gene IFN can augment oncolytic effects while minimizing systemic toxicity. Methods IFN-expressing vectors were tested in vitro with the use of 4 PDAc cell lines with cytocidal effect measured by crystal violet and colorimetrically and IFN production assayed by ELISA. Cox2 promoter activity was checked by a luciferase reporter assay. In vivo, subcutaneous tumor xenografts with 2 PDAc cell lines in nude mice were treated with a single intratumoral viral dose. Results All PDAc cell lines were Cox2-positive. Oncolysis from the novel Cox2-controlled virus was comparable or superior to Adwt, the wild-type virus without safety features. The absence of cytocidal effect in Cox2-negative cells with the novel virus indicated cancer specificity. In vivo, stronger tumor suppression from the novel virus was seen when compared with nonreplicating IFN-expressing vectors. Conclusion We demonstrated the potent therapeutic effects of a novel tumor-specific conditionally replicative IFN-expressing adenovirus. With potential to locally deliver IFN and avoid systemic toxicity, this strategy may therefore expand the application of this robust and promising therapy.

Summary Objectives In recent years, the incidence of Human Papilloma Virus (HPV)-positive head and neck squamous cell carcinomas (HNSCC) has markedly increased. Our aim was to design a novel therapeutic agent through the use of conditionally replicative adenoviruses (CRAds) that are targeted to the HPV E6 and E7 oncoproteins. Methods Each adenovirus included small deletion(s) in the E1a region of the genome (Δ24 or CB016) intended to allow for selective replication in HPV-positive cells. In vitro assays were performed to analyze the transduction efficiency of the vectors and the cell viability following viral infection. Then, the UPCI SCC090 cell line (HPV-positive) was used to establish subcutaneous tumors in the flanks of nude mice. The tumors were then treated with either one dose of the virus or four doses (injected every fourth day). Results The transduction analysis with luciferase-expressing viruses demonstrated that the 5/3 fiber modification maximized virus infectivity. In vitro, both viruses (5/3Δ24 and 5/3CB016) demonstrated profound oncolytic effects. The 5/3CB016 virus was more selective for HPV-positive HNSCC cells, whereas the 5/3Δ24 virus killed HNSCC cells regardless of HPV status. In vivo, single injections of both viruses demonstrated anti-tumor effects for only a few days following viral inoculation. However, after four viral injections, there was statistically significant reductions in tumor growth when compared to the control group (p Conclusion CRAds targeted to HPV-positive HNSCCs demonstrated excellent in vitro and in vivo therapeutic effects, and they have the potential to be clinically translated as a novel treatment modality for this emerging disease.

Background The addition of interferon (IFN) alpha to adjuvant chemoradiotherapy regimens resulted in remarkable improvements in survival for pancreatic cancer patients. However, systemic toxicities and insufficient levels of IFN at the tumor sites have limited its widespread adoption in treatment schemes. We have previously developed an IFN-expressing conditionally replicative oncolytic adenovirus and demonstrated its therapeutic effects both in vitro and in vivo. Here, the same vectors were tested in a syngeneic and immunocompetent Syrian hamster model to better understand the roles of adenoviral replication and of the pleiotropic effects of IFN on pancreatic tumor growth suppression. Methods Oncolytic adenoviruses expressing human or hamster IFN were designed and generated. Viral vectors were tested in vitro to determine qualitative and quantitative cell viability, cyclooxygenase 2 (Cox2) promoter activity, and IFN production. For the in vivo studies, subcutaneous hamster pancreatic cancer tumors were treated with 1 intratumoral dose of virus. Similarly, 1 intraperitoneal dose of virus was used to prolong survival in a carcinomatosis model. Results All cell lines tested demonstrated Cox2 promoter activity. The oncolytic potential of a replication competent adenovirus expressing the IFN cytokine was clearly demonstrated. These viruses resulted in significant tumor growth suppression and survival increases compared with controls in a hamster model. Conclusion The profound therapeutic potential of an IFN-expressing oncolytic adenovirus for the treatment of pancreatic cancer was demonstrated in a syngeneic Syrian hamster model. These results strongly suggest the potential application of our viruses as part of combination regimens with other therapeutics.

Aside from curative resection, there is no curative treatment against pancreatic adenocarcinoma (PDAC) at present. Late diagnosis and high recurrence results in five-year survival of 6%. Notably, Phase II trials based on adjuvant therapy combining systemic IFN Alpha (IFN) and chemoradiation reported 30-50% increase in two-year survival and impressive 35% increase in five-year survival of PDAC patients. Despite promising results, trial drawbacks included high patient dropout due to IFN systemic toxicity and low IFN levels in tumors. Low intratumoral IFN hampered the full potential of the therapy while IFN is known to induce tumor apoptosis, chemoradio sensitization, and decreased tumor neo-vasculatization.Aiming to improve efficacy and tolerability of IFN therapy, we have developed an oncolytic adenovirus expressing human IFN (OAd-IFN). Vector has Ad5/3 fiber modification and overexpresses Adenoviral Death Protein respectively contributing to increased infectivity and oncolysis. Taking advantage of Cox-2 up-regulation in PDAC, the Cox-2 promoter was included in the upstream of Adenovirus E1 region, restricting vector replication to cancer cells. Human IFN-alpha gene was placed in the Adenovirus E3 region in the way that its expression is controlled by the adenovirus major late promoter. Therefore, IFN expression in this vector is replication dependent. To test the vector in an immunocompetent syngeneic hamster model of pancreatic cancer, OAd-IFN expressing hamster IFN was generated. Vector contains RGD fiber modification enhancing its infectivity in hamster cells.MTS and crystal violet assays demonstrated sensitization of PDAC cells to chemotherapy (5-FU, Cisplatin, and Gemcitabine), and radiation (4 and 8Gy) by OAd-IFN. Comparison between OAd-IFN and control vector not expressing IFN (OAd-LUC) indicated that IFN expressed by OAd-IFN is functional in combination therapy sensitizing PDAC cells to chemoradiation. Colony formation assay showed that combinations of OAd-IFN with chemotherapy, radiation, or chemoradiation are synergistic and exhibit superior killing effect compared to groups without OAd-IFN.In vivo studies using immunocompetent syngeneic hamster model of pancreatic cancer showed that combinations including OAd-IFN resulted in augmented tumor shrinkage and survival compared to groups treated with chemotherapy, radiation, chemoradiation, or OAd-LUC + radiation. Hexon staining and viral DNA quantification by qPCR show OAd-IFN effectively replicates and spreads in tumors.Our data suggests OAd-IFN synergistically improves chemoradioation in PDAC cells, and shows superior therapeutic effect when treating immunocompetent model of pancreatic cancer. Vector capacity to express high levels of IFN intratumorally and the strong synergism between OAd-IFN and radiation, chemotherapy, and chemoradiation indicates OAd-IFN will contribute to more olerable and effective IFN therapy. Strong synergism between OAd-IFN and chemoradiation combined with focal expression of IFN can help to reduce not only IFN toxicity, but also dose-dependent toxicity of chemoradiation. Considering systemic IFN injection combined with chemoradiation is one of the few therapies to effectively treat pancreatic cancer, usage of OAd-IFN in combination with chemoradiation has great potential to result in more effective and tolerable therapy agaisnt pancreatic cancer.

Introduction:Recent reports have shown that the incidence of Human Papilloma Virus (HPV)-positive head and neck squamous cell carcinomas (HNSCC) has been steadily increasing. HNSCCs are known to have a high recurrence rate and compared to their HPV-negative counterparts, these tumors have a unique biology which necessitates the development of novel treatment modalities. The HPV E6 and E7 oncoproteins are attractive therapeutic targets as they interact with key cell cycle regulatory components, namely p53 and pRb. Our research group has applied conditionally replicating oncolytic adenoviruses (CRAd) with modifications in the E1a region of the genome allowing for selective replication in E6 and E7 expressing HNSCCs.Methods:The in vitro transduction efficiency of E1-deleted luciferase expressing vectors with fiber modifications was assessed in multiple HPV-positive and negative cell lines. The CRAds were designed with a distinct deletion in the E1a region of the adenoviral genome (D24 and CB016) intended to allow for selective replication in HPV-positive HNSCC cells. Additionally, the CRAds have a luciferase transgene in the E3 region that is expressed in a replication dependent manner. By using a luciferase assay, the degree of viral replication was analyzed in numerous HNSCC cell lines. In vitro cell viability following viral infection was analyzed with crystal violet and MTS assays. A HPV-positive cell line (UPCI SCC 090) was used to establish subcutaneous tumors in female nude mice. They were subsequently treated with either one intratumoral viral injection or four injections (given every fourth day).Results:The 5/3 fiber modification significantly increased viral infectivity in all tested HNSCC cell lines. The 5/3 CB016 vector replicated selectively in HPV-positive cell lines, while the 5/3 D24 virus replicated in all cell lines regardless of HPV status. Both of the vectors demonstrated profound cytocidal effects in the crystal violet and MTS assays. For the in vivo experiments, a single intratumoral injection of virus demonstrated an anti-tumor effect for only one week following injection. Given this limited effect, an additional in vivo experiment was performed to analyze the efficacy of multiple intratumoral injections (3.5 x1011 vp/injection). This setup resulted in statistically significant tumor growth suppression at day 26 when compared to the saline control group (p

Background/objective. There has recently been such great interest in cancer incidence among the semiconductor workers. Therefore, an epidemiological study was conducted to figure out the cancer incidence rate among semiconductor workers and potential factors affecting cancer. Methods. The study was performed for the semiconductor workers employed from 1999 to 2008, and the total number of workers in a cohort was 56,283 who employed for over one month. Cancer incidence rate was analyzed by departments, divisions, job titles, gender, age, viral hepatitis and working duration. We compared the incidence of hematological cancer in this cohort with that expected on the basis of cancer incidence in the general population. Results. Overall, the standardized incidence rate (SIR) for workers indicates 0.76 (95% CI: 0.66-0.86) compared to general population data. In particular, the rate for leukemia was 0.86(0.50-1.47) in the total. Non-Hodgkin's lymphoma was observed high SIR which was not statistically significant among female assembly workers(2.42, 95% CI: 0.78-7.49), whereas in office workers were significant high (5.23, 95% CI: 1.31-20.92). We also found that the hepatitis virus affected in female workers (7.69, 95% CI: 1.08-54.60). Conclusions. We concluded that the SIR for non-Hodgkin's lymphoma among female workers is high because of personal factors and additional research works are considered for some confounder factors. Epidemiological study based on a constant, long-term prospective cohort is required for the future studies. Citation Format: Kyoungho Lee, Joohee Han, Kwansick Kim, Soo-Geun Kim. Hematological cancer incidence among semiconductor workers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 125. doi:10.1158/1538-7445.AM2013-125

Adenovirus (Ad) has frequently been used as a backbone of oncolytic viral agents, while lack of selectivity to cancer cells at the stage of infection has greatly hampered in vivo efficacy. Unlike loco-regional therapy, systemic application of cancer gene therapy mandates different level of selectivity of gene delivery. The controlled distribution and selective transduction of the vector would overcome the obstacles for systemic delivery and enable efficient systemic treatment of cancer. We have recently developed transductionally-targeted Ads by high-throughput screening of high-diversity (10ˆ9-level) Ad-library. Mesothelin (MSLN) is highly over-expressed in pancreatic cancers. Ad with redesigned AB-loop targeting MSLN, AdML-VTIN, was successfully isolated from the high throughput screening of Ad library by infectivity for MSLN-expressing 293 cells (293-MSLN). The in vitro binding of AdML-VTIN corresponded to the level of MSLN-expression and the suppression of MSLN with siRNA or antibody significantly reduced the binding to MSLN-expressing cells, which indicates that mesothelin is a receptor moiety for the isolated targeting ligand. The binding ability of this virus in Panc-1 (MSLN-positive) was higher than that of Ad with 5/3 modified fiber which is known to exhibit highest infectivity in pancreatic cancer cells. The in vivo antitumor effect was compared in Panc-1 and MiaPaCa-2 (MSLN-negative) subcutaneous xenografts. The injection of the MSLN-retargeted oncolytic Ad showed significant antitumor effect against Panc-1 tumors, and about half of the tumor disappeared. Contrarily, the same virus showed no antitumor effect in MiaPaCa-2. Viral DNA quantitation also supported the selective viral replication in Panc-1. Upon systemic administration in the nude mice with Panc-1 subcutaneous xenografts, the sequestration of AdML-VTIN to the liver was significantly lower than that of wild-type Ad5, and the copy number of this retargeted virus was significantly (1000 fold) higher in the tumor. These data indicates the systemic delivery of this vector is efficient for MSLN-expression pancreatic cancer xenografts. In this study, our MSLN-targeted Ad vector exhibited significant infectivity to MSLN-positive pancreatic cancer cells in vitro and in vivo. Moreover, this virus showed significantly reduced liver sequestration as well as dramatically augmented delivery to the tumors upon systemic administration. This new genetically modified Ad transductionally retargeted to pancreatic cancer may embody a next generation targeting for this devastating disease in clinical settings. Citation Format: Yoshiaki Miura, Joohee Han, Julia Davydova, Masato Yamamoto. Systemic administration of fiber redesigned infectivity-selective oncolytic adenovirus for pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3308. doi:10.1158/1538-7445.AM2013-3308 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

s / Pancreatology 13 (2013) e1–e94 e22 Methods:We assembled an islet isolation laboratory within a large operating room where the pancreatectomies were performed. This consisted of a hooded workstation (Labconco Class II Type A2), a centrifuge (Beckman Coulter Allegra 25R), and an islet isolation system (BiorepRicordi Islet Isolator) comparable to thoseused in thestandard laboratorysetting.Apancreatectomy was performed with immediate isolation of the islets within the operating room. As soon as the islets were suspended in the final preparation solution, they were infused into the portal venous system. The gastrojejunostomy and hepaticojejunostomywereperformedduring the intraoperative islet isolation. Results: We report 8 patients who underwent successful intraoperative islet isolation with reinfusion over an 8-month period (8/2011 – 4/2012). Mean total operative time was 8.8 hrs (range 7.3 13 hrs). Mean islet equivalent (IEQ) yield was 707,235 islets (range 250,000-1,400,000 islets). Of these, 88% (7/8) are producing C peptide. Conclusion:We describe the first report of a totally intraoperative islet isolation series, which eliminates the time, cost and risk of processing the gland in a separate remote laboratory. Intraoperative islet isolation resulted in comparable islet yield to that described with utilization of a remote laboratory. The transplanted islets using this novel technique had a good functional outcome.

Immigrants and their native-born children often face considerable wage penalties relative to natives, but less is known about whether this inequality arises through differences in educational qualifications, unequal sorting across occupations, and establishments, or differential pay for the same work. Using linked employer–employee data from Norway, we ask (a) whether immigrant–native wage gaps reflect in differences in education, sorting, or within-job pay, (b) whether wage gaps differ by immigrant generation, and (c) whether wage gaps vary across different segments of the labor market. We find that immigrant–native wage inequality primarily reflects sorting into lower-paying jobs and wage gaps are considerably reduced across immigrant generations. When doing the same work for the same employer, immigrant-background workers, especially children of immigrants, earn similar wages to natives. Sorting into jobs seems more meritocratic for university graduates, professionals, and in the public sector, but within-job pay differentials are strikingly similar across market segments.