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At least 649 records · Page 36Linked to original sources
PubMed2005

Recombinant human immunodeficiency virus type 1 integrase exhibits a capacity for full-site integration in vitro that is comparable to that of purified preintegration complexes from virus-infected cells.

Retrovirus preintegration complexes (PIC) in virus-infected cells contain the linear viral DNA genome (approximately 10 kbp), viral proteins including integrase (IN), and cellular proteins. After transport of the PIC into the nucleus, IN catalyzes the concerted insertion of the two viral DNA ends into the host chromosome. This successful insertion process is termed "full-site integration." Reconstitution of nucleoprotein complexes using recombinant human immunodeficiency virus type 1 (HIV-1) IN and model viral DNA donor substrates (approximately 0.30 to 0.48 kbp in length) that are capable of catalyzing efficient full-site integration has proven difficult. Many of the products are half-site integration reactions where either IN inserts only one end of the viral donor substrate into a circular DNA target or into other donors. In this report, we have purified recombinant HIV-1 IN at pH 6.8 in the presence of MgSO4 that performed full-site integration nearly as efficiently as HIV-1 PIC. The size of the viral DNA substrate was significantly increased to 4.1 kbp, thus allowing for the number of viral DNA ends and the concentrations of IN in the reaction mixtures to be decreased by a factor of approximately 10. In a typical reaction at 37 degrees C, recombinant HIV-1 IN at 5 to 10 nM incorporated 30 to 40% of the input DNA donor into full-site integration products. The synthesis of full-site products continued up to approximately 2 h, comparable to incubation times used with HIV-1 PIC. Approximately 5% of the input donor was incorporated into the circular target producing half-site products with no significant quantities of other integration products produced. DNA sequence analysis of the viral DNA-target junctions derived from wild-type U3 and U5 coupled reactions showed an approximately 70% fidelity for the HIV-1 5-bp host site duplications. Recombinant HIV-1 IN successfully utilized a mutant U5 end containing additional nucleotide extensions for full-site integration demonstrating that IN worked properly under nonideal active substrate conditions. The fidelity of the 5-bp host site duplications was also high with these coupled mutant U5 and wild-type U3 donor ends. These studies suggest that recombinant HIV-1 IN is at least as capable as native IN in virus particles and approaching that observed with HIV-1 PIC for catalyzing full-site integration.

Base Sequence↗
PubMed2005

Large-scale analysis of adeno-associated virus vector integration sites in normal human cells.

The integration sites of viral vectors used in human gene therapy can have important consequences for safety and efficacy. However, an extensive evaluation of adeno-associated virus (AAV) vector integration sites has not been completed, despite the ongoing use of AAV vectors in clinical trials. Here we have used a shuttle vector system to isolate and analyze 977 unique AAV vector-chromosome integration junctions from normal human fibroblasts and describe their genomic distribution. We found a significant preference for integrating within CpG islands and the first 1 kb of genes, but only a slight overall preference for transcribed sequences. Integration sites were clustered throughout the genome, including a major preference for integration in ribosomal DNA repeats, and 13 other hotspots that contained three or more proviruses within a 500-kb window. Both junctions were localized from 323 proviruses, allowing us to characterize the chromosomal deletions, insertions, and translocations associated with vector integration. These studies establish a profile of insertional mutagenesis for AAV vectors and provide unique insight into the chromosomal distribution of DNA strand breaks that may facilitate integration.

Chromosome Mapping↗
PubMed2004

Acquisition of high-level chromosomal instability is associated with integration of human papillomavirus type 16 in cervical keratinocytes.

Whereas two key steps in cervical carcinogenesis are integration of high-risk human papillomavirus (HR-HPV) and acquisition of an unstable host genome, the temporal association between these events is poorly understood. Chromosomal instability is induced when HR-HPV E7 oncoprotein is overexpressed from heterologous promoters in vitro. However, it is not known whether such events occur at the "physiologically" elevated levels of E7 produced by deregulation of the homologous HR-HPV promoter after integration. Indeed, an alternative possibility is that integration in vivo is favored in an already unstable host genome. We have addressed these issues using the unique human papillomavirus (HPV) 16-containing cervical keratinocyte cell line W12, which was derived from a low-grade squamous intraepithelial lesion and thus acquired HPV16 by "natural" infection. Whereas W12 at low passage contains HPV16 episomes only, long-term culture results in the emergence of cells containing integrated HPV16 only. We show that integration of HPV16 in W12 is associated with 3' deletion of the E2 transcriptional repressor, resulting in deregulation of the homologous promoter of the integrant and an increase in E7 protein levels. We further demonstrate that high-level chromosomal instability develops in W12 only after integration and that the forms of instability observed correlate with the physical state of HPV16 DNA and the level of E7 protein. Whereas intermediate E7 levels are associated with numerical chromosomal abnormalities, maximal levels are associated with both numerical and structural aberrations. HR-HPV integration is likely to be a critical event in cervical carcinogenesis, preceding the development of chromosomal abnormalities that drive malignant progression.

Cells, Cultured↗
PubMed2004

Improving access to geriatric mental health services: a randomized trial comparing treatment engagement with integrated versus enhanced referral care for depression, anxiety, and at-risk alcohol use.

OBJECTIVE: The authors sought to determine whether integrated mental health services or enhanced referral to specialty mental health clinics results in greater engagement in mental health/substance abuse services by older primary care patients. METHOD: This multisite randomized trial included 10 sites consisting of primary care and specialty mental health/substance abuse clinics. Primary care patients 65 years old or older (N=24,930) were screened. The final study group consisted of 2,022 patients (mean age=73.5 years; 26% female; 48% ethnic minority) with depression (N=1,390), anxiety (N=70), at-risk alcohol use (N=414), or dual diagnosis (N=148) who were randomly assigned to integrated care (mental health and substance abuse providers co-located in primary care; N=999) or enhanced referral to specialty mental health/substance abuse clinics (i.e., facilitated scheduling, transportation, payment; N=1,023). RESULTS: Seventy-one percent of patients engaged in treatment in the integrated model compared with 49% in the enhanced referral model. Integrated care was associated with more mental health and substance abuse visits per patient (mean=3.04) relative to enhanced referral (mean=1.91). Overall, greater engagement was predicted by integrated care and higher mental distress. For depression, greater engagement was predicted by integrated care and more severe depression. For at-risk alcohol users, greater engagement was predicted by integrated care and more severe problem drinking. For all conditions, greater engagement was associated with closer proximity of mental health/substance abuse services to primary care. CONCLUSIONS: Older primary care patients are more likely to accept collaborative mental health treatment within primary care than in mental health/substance abuse clinics. These results suggest that integrated service arrangements improve access to mental health and substance abuse services for older adults who underuse these services.

Age Factors↗
PubMed1999

Development of a vertically integrated program of services for persons with schizophrenia.

Economic pressures are changing the nature and quality of services available to individuals with chronic psychiatric disorders. Vertical integration of services has been proposed as a strategy for cost-effective merging of resources. This report describes the integration of inpatient, continuing day treatment, and ambulatory clinic services over an 18-month period into a service line for patients with schizophrenia. Key principles in implementing the integrated program included an open admission policy, continuity of care, use of criteria for level of care that were set by external review agencies, rapid transfers between services, and maintenance of the integrity of the treatment plan. Steps toward integration included evaluating and securing treatment resources, establishing core treatment approaches, fostering staff development, implementing outcomes assessment, and presenting the new program to clients, family members, and the community. The integrated program was 15 percent more productive than the combined services before integration, and inpatient length of stay dropped by 66 percent. Vertical integration of services is cost-effective and offers the potential for significant clinical benefits.

Continuity of Patient Care↗
PubMed2004

Promoter trapping reveals significant differences in integration site selection between MLV and HIV vectors in primary hematopoietic cells.

Recent reports have indicated that human immunodeficiency virus (HIV) and murine leukemia virus (MLV) vectors preferentially integrate into active genes. Here, we used a novel approach based on genetic trapping to rapidly score several thousand integration sites and found that MLV vectors trapped cellular promoters more efficiently than HIV vectors. Remarkably, 1 in 5 MLV integrations trapped an active promoter in different cell lines and primary hematopoietic cells. Such frequency was even higher in growth-stimulated lymphocytes. We show that the different behavior of MLV and HIV vectors was dependent on a different integration pattern within transcribed genes. Whereas MLV-based traps showed a strong bias for promoter-proximal integration leading to efficient reporter expression, HIV-based traps integrated throughout transcriptional units and were limited for expression by the distance from the promoter and the reading frame of the targeted gene. Our results indicate a strong propensity of MLV to establish transcriptional interactions with cellular promoters, a behavior that may have evolved to enhance proviral expression and may increase the insertional mutagenesis risk. Promoter trapping efficiency provides a convenient readout to assess transcriptional interactions between the vector and its flanking genes at the integration site and to compare integration site selection among different cell types and in different growth conditions.

Cell Line↗
PubMed2005

Preferential selection of human T-cell leukemia virus type I provirus integration sites in leukemic versus carrier states.

Human T-cell leukemia virus type I (HTLV-I) is a causative agent of neoplastic disease, adult T-cell leukemia (ATL). Although the encoding viral proteins play an important role in oncogenesis, the role of the HTLV-I proviral integration site remains unsolved. We determined the integration sites of HTLV-I proviruses in ATL cells and HTLV-I-infected cells in asymptomatic carriers. In carrier and ATL cells, HTLV-I provirus was integrated into the transcriptional unit at frequencies of 26.8% (15/56) and 33.9% (20/59), respectively, which were equivalent to the frequency calculated based on random integration (33.2%). In addition, HTLV-I provirus was prone to integration near the transcriptional start sites in leukemic cells (P = .006), and the transcriptional direction of the provirus was in accordance with that of integrated cellular genes in 70% of cases. More importantly, the integration sites in the carrier cells favored the alphoid repetitive sequences (11/56; 20%) whereas in leukemic cells they disfavored these sequences (2/59; 3.4%). Taken together, during natural course from carrier to onset of ATL, HTLV-I-infected cells with integration sites favorable for viral gene transcription are susceptible to malignant transformation due to increased viral gene expression.

Base Sequence↗
PubMed2002

Human papilloma viruses and cervical tumours: mapping of integration sites and analysis of adjacent cellular sequences.

BACKGROUND: In cervical tumours the integration of human papilloma viruses (HPV) transcripts often results in the generation of transcripts that consist of hybrids of viral and cellular sequences. Mapping data using a variety of techniques has demonstrated that HPV integration occurred without obvious specificity into human genome. However, these techniques could not demonstrate whether integration resulted in the generation of transcripts encoding viral or viral-cellular sequences. The aim of this work was to map the integration sites of HPV DNA and to analyse the adjacent cellular sequences. METHODS: Amplification of the INTs was done by the APOT technique. The APOT products were sequenced according to standard protocols. The analysis of the sequences was performed using BLASTN program and public databases. To localise the INTs PCR-based screening of GeneBridge4-RH-panel was used. RESULTS: Twelve cellular sequences adjacent to integrated HPV16 (INT markers) expressed in squamous cell cervical carcinomas were isolated. For 11 INT markers homologous human genomic sequences were readily identified and 9 of these showed significant homologies to known genes/ESTs. Using the known locations of homologous cDNAs and the RH-mapping techniques, mapping studies showed that the INTs are distributed among different human chromosomes for each tumour sample and are located in regions with the high levels of expression. CONCLUSIONS: Integration of HPV genomes occurs into the different human chromosomes but into regions that contain highly transcribed genes. One interpretation of these studies is that integration of HPV occurs into decondensed regions, which are more accessible for integration of foreign DNA.

Binding Sites↗
PubMed1996

Health system integration: a means to an end.

The creation of integrated firms and contractual networks in health care often is a precondition for other forms of integration that could actually lower costs and improve quality of care. Although different types of integration activities are leading to innovations in the production of services and the care of populations, the continued influence of the "old" indemnity insurance/fee-for-service system creates important obstacles to those integration activities. If creation of integrated firms and contractual networks races ahead of other forms of integration, it could produce uncompetitive markets that reduce pressures to integrate in ways that can cut costs and improve quality of care. Purchasers' actions could play a major role in determining the future of various integration activities.

Community Health Planning↗
PubMed2026

A nonlinear multi-omics data integration and classification model based on pathway self-attention and graph convolutional networks.

The abundance of omics data has significantly advanced the development of multi-omics data integration techniques. Non-linear embedding approaches for data integration have gradually become the mainstream in multi-omics research, as these approaches can substantially improve cancer analysis by enhancing the quality of the embeddings. However, current multi-omics data integration methods are typically confined to omics measurements, neglecting domain-specific prior knowledge encompassing biological pathways. In this study, we proposed a multi-omics integrated classification model, PathTransGCN, based on pathway self-attention and graph convolutional networks (GCN). The model integrated biological pathway information into multi-omics data analysis with the aim of enhancing the accuracy of cancer classification. Multi-omics data for breast cancer (BRCA), non-small cell lung cancer (NSCLC), and low-grade glioma (LGG) were obtained from The Cancer Genome Atlas (TCGA) and UCSC Xena databases. These data included gene mutations, DNA methylation, copy number variations, and gene expression, and were used to assess the model's generalizability across different cancers. First, PathTransGCN employed a pathway self-attention module to learn latent representations of samples across different pathways, thereby obtaining multi-omics integration vectors. Concurrently, a patient similarity network (PSN) was constructed using the similarity network fusion (SNF) approach. Second, the integrated vectors and the PSN were jointly fed into a GCN for end-to-end training, enabling precise classification of cancer subtypes. Through multi-omics data analysis of the BRCA dataset, PathTransGCN outperformed several popular algorithms (such as MoGCN and DeePathNet) in the five-class classification of cancer subtypes, achieving an accuracy rate of 87.6% and an F1 score of 86.4%. Moreover, the model demonstrated robust generalization capabilities across both NSCLC and LGG datasets, while effectively identifying key disease-associated biomarkers at the pathway level. Experimental results demonstrate that PathTransGCN exhibits outstanding performance in integrating omics data and delivering interpretable classification outcomes, presenting significant potential for clinical applications.

Humans↗
PubMed1997

The effect of a new integrated mental health service on hospitalisation.

OBJECTIVE: The purpose of the present study was to partially evaluate a new integrated mental health service by monitoring inpatient lengths of stay. We hypothesised that the median cumulated length of stay for inpatients would decrease, and that the frequency of readmissions would not increase. METHOD: Data was collected for two 6-month periods before and after the introduction of an integrated mental health service (IMHS). Two functionally identical wards (G and E) were studied. Ward G was then integrated with the regional community psychiatry service, while Ward E remained non-integrated. RESULTS: Following integration, the median cumulative length of stay in the IMHS's Ward G was more than halved in comparison with both its own baseline and with the non-integrated ward. The average length of stay of overdose patients at the regional general hospital that was serviced by the IMHS was also reduced from 2.6 days to 1.5 days. The non-IMHS ward had a non-significant increase in admissions and no change in cumulative length of stay. CONCLUSION: The hypotheses of this study were supported by the results. Twelve beds were subsequently closed as a result of the efficiencies generated by integration. These findings support the model of true integration trailled here.

Australia↗
PubMed1995

Loosening the Gordian Knot of governance in integrated health care delivery systems.

A new organizational species is emerging--the integrated health care delivery system. Aligned with both the anticipated provisions of federal and state health care reform initiatives and emerging purchaser demands, integrated delivery systems could dominate many health care markets by the end of this decade. Integration is both the defining feature and key imperative of such systems. Because of the unique position of boards, governance is potentially the ultimate integrator. Yet little attention had been focused on integrated delivery system governance. Accordingly, this article will address the governance of integrated delivery systems through three questions: (1) What are the distinguishing characteristics of integrated health care delivery systems? (2) What are the distinctive issues and challenges associated with governing integrated delivery systems? and (3) What different forms of governance can be employed by these systems and what factors influence the effectiveness of these forms?

American Hospital Association↗
PubMed1997

Organization design of integrated delivery systems.

Healthcare integrated delivery systems (IDSs) evolve through four observed stages of development, with each successive stage having greater levels of interdependence among facilities and between facilities and physicians. The cottage industry stage is characterized by competition among hospitals and little interdependence. Healthcare organizations in the next stage, horizontally integrated systems, have pooled interdependencies, and in the third stage, vertically integrated systems, have predominately sequential interdependence with reciprocal interdependence between physicians and hospitals. In the fourth stage, community healthcare, community systems have reciprocal interdependence among their facilities and other organizations providing services along the continuum of care. This reciprocal interdependence is characteristic of the level of integration that must be addressed for system effectiveness. Greater levels of interdependence require stronger organizational integrating mechanisms and processes. "Integrative management" or "service-line management" is one vehicle for providing this integration. Although few empirical studies are available, this article relates the available empirical and conceptual literature to analyze the interdependencies at each level of IDS development, as well as the organizational design characteristics to address those interdependencies. It then examines the organization of the Veterans Health Administration (VHA) in terms of the four stages of IDS evolution, and suggests organization designs to address VHA's increased needs for integration.

Community Networks↗
PubMed1998

Three-tiered integration of PACS and HIS toward next generation total hospital information system.

The Seoul National University Hospital (SNUH) started a project to innovate the hospital information facilities. This project includes installation of high speed hospital network, development of new HIS, OCS (order communication system), RIS and PACS. This project aims at the implementation of the first total hospital information system by seamlessly integrating these systems together. To achieve this goal, we took three-tiered systems integration approach: network level, database level, and workstation level integration. There are 3 loops of networks in SNUH: proprietary star network for host computer based HIS, Ethernet based hospital LAN for OCS and RIS, and ATM based network for PACS. They are linked together at the backbone level to allow high speed communication between these systems. We have developed special communication modules for each system that allow data interchange between different databases and computer platforms. We have also developed an integrated workstation in which both the OCS and PACS application programs run on a single computer in an integrated manner allowing the clinical users to access and display radiological images as well as textual clinical information within a single user environment. A study is in progress toward a total hospital information system in SNUH by seamlessly integrating the main hospital information resources such as HIS, OCS, and PACS. With the three-tiered systems integration approach, we could successfully integrate the systems from the network level to the user application level.

Hospital Information Systems↗
PubMed1999

Integrating reproductive health: myth and ideology.

Since 1994, integrating human immunodeficiency virus/sexually transmitted disease (HIV/STD) services with primary health care, as part of reproductive health, has been advocated to address two major public health problems: to control the spread of HIV; and to improve women's reproductive health. However, integration is unlikely to succeed because primary health care and the political context within which this approach is taking place are unsuited to the task. In this paper, a historical comparison is made between the health systems of Ghana, Kenya and Zambia and that of South Africa, to examine progress on integration of HIV/STD services since 1994. Our findings indicate that primary health care in Ghana, Kenya and Zambia has been used mainly by women and children and that integration has meant adding new activities to these services. For the vertical programmes which support these services, integration implies enhanced collaboration rather than merged responsibility. This compromise between comprehensive rhetoric and selective reality has resulted in little change to existing structures and processes; problems with integration have been exacerbated by the activities of external donors. By comparison, in South Africa integration has been achieved through political commitment to primary health care rather than expanding vertical programmes (top-down management systems). The rhetoric of integration has been widely used in reproductive health despite lack of evidence for its feasibility, as a result of the convergence of four agendas: improving family planning quality; the need to improve women's health; the rapid spread of HIV; and conceptual shifts in primary health care. International reproductive health actors, however, have taken little account of political, financial and managerial constraints to implementation in low-income countries.

Adult↗
PubMed2002

A process for specifying integration for multi-tier applications in healthcare.

Integrating heterogeneous application systems in healthcare is needed to support clinical work, patient-centric care, regional interoperability and utilization of both valuable legacy systems and new technologies. The integration process is quite complicated, and must be supported by flexible integration processes and methods. The integration methods should support evaluation and specification of different integration approaches and technologies on many different interoperability levels. We introduce a process for specifying many integration decisions for a given integration situation. The process is part of an integration method, which is validated in PlugIT project in Finland.

Delivery of Health Care↗
PubMedDate not supplied

Integrative healthcare: arriving at a working definition.

A variety of integrative healthcare programs and clinics have been initiated both in Canada and the United States. Many different terms (eg, integrative medicine, integrated medicine, multidisciplinary care, integrative health care) are used to describe these initiatives. The diversity of terminology and absence of a shared conceptual framework makes it difficult to assess when integration is actually happening. The objective of this paper was to explore current efforts to conceptualize integrative healthcare and to identify its components. A qualitative content analysis of articles identified in an extensive literature review resulted in the identification of four key components of integrative care: philosophy/values, structure, process and outcomes. These were used to guide the development of a definition of integrative healthcare that should be seen as an "ideal type" or goal toward which practitioners and health systems could strive.

Canada↗
PubMed1996

Frequency and distribution of chromosomal integration sites of the Epstein-Barr virus genome.

Human lymphocytes can be transformed in vitro by integration of the Epstein-Barr virus (EBV) into the host genome. To study whether integration sites are stable or changeable in the course of long-term cultivation, three EBV-transformed lymphoblastoid cell lines, along with positive control (Namalwa cell line) and negative control (noninfected lymphocytes) cells were studied. A biotinylated Bam H1WEBV-DNA fragment was used as the probe for fluorescence in situ hybridization to count the numbers and to localize the sites of integrated EBV-DNA. Among these cell lines, the percentage of cells with integrated signals varied from 58% to 91%, with a mean of 1.43 to 2.66 signals per cell. No consistent tendency of increasing or decreasing number of signals was observed for the three cell lines harvested at four different cultivation intervals (86-204 days after infection). Although the integration was not site-specific, high frequencies of integration did occur in all three cell lines at the following chromosomal sites: 1p31, 1q31, 2q32, 3q13, 6q24 and 7q31. Because there were multiple integration sites present, it was difficult to draw any conclusion on integration site stability.

Adult↗