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Antiretroviral therapy (ART) fails to fully restore immune function and is not curative. A single infusion of CCR5 gene-edited autologous CD4+ T cells (SB-728-T) led to sustained increases in CD4+ T cell counts, improved T cell homeostasis, and reduced the estimated size of the HIV reservoir. These outcomes were associated with the expansion and long-term persistence of a novel CCR5 gene-edited CD4+ T memory stem cell (CD45RAintROint TSCM) subset that can replenish the pool of more differentiated memory cells. We showed that novel CD45RAintROint TSCM cells are transcriptionally distinct from the previously described CD45RA+ TSCM and are minimally differentiated cells uncommitted to a specific Th-lineage. Subsequently, we showed in an independent trial that infusion of the SB-728-T cell product resulted in partial control of viral replication upon cessation of ART which was correlated with the frequencies of CCR5 gene-edited TSCM and their TEM progeny. Interestingly, one participant that remained off ART to this date demonstrated long-term maintenance of CCR5 gene-edited cells and increased frequency of polyfunctional HIV-specific CD4+ and CD8+ T cells, contributing to low levels of viral load 5 years post-infusion. Consequently, the generation of HIV protected memory CD4+ T cells by CCR5 disruption can contribute toward novel interventions aimed at achieving a sustained ART-free viral remission of HIV disease.

Objective: To provide a clinical practice guideline with the latest evidence for diagnosis and treatment of nonalcoholic fatty liver disease for patients, caregivers, administrative and government bodies at all levels of care in Colombia. Materials and Methods: This guide was developed by a multidisciplinary team with the support of the Colombian Association of Gastroenterology, Cochrane STI Group and Clinical Research Institute of the Universidad Nacional de Colombia. Relevant clinical questions were developed and the search for national and international guidelines in databases was performed. Existing guidelines were evaluated about quality and applicability. One guideline met the criteria for adaptation, so the group decided to adapt 3 clinical questions. Systematic literature searches were conducted by the Cochrane Group. The tables of evidence and recommendations were made based on the GRADE methodology. The recommendations of the guide were socialized in a meeting of experts with government agencies and patients. Results: An evidence-based Clinical Practice Guidelines for the diagnosis and treatment of nonalcoholic fatty liver disease was developed for the Colombian context. Conclusions: The opportune detection and appropriate management of nonalcoholic fatty liver disease would contribute to the burden of the disease in Colombia. © 2015 Asociaciones Colombianas de Gastroenterología, Endoscopia digestiva, Coloproctología y Hepatología.

Objective: To provide an evidence-based clinical practice guideline for the management of dyspepsia for patients, caregivers, administrative and government bodies at all levels of care in Colombia. Materials and Methods: This guide was developed by a multidisciplinary team with the support of the Colombian Association of Gastroenterology, Cochrane STI Group and Clinical Research Institute of the Universidad Nacional de Colombia. Relevant clinical questions were developed and the search for national and international guidelines in databases was performed. Existing guidelines were evaluated for quality and applicability. One guideline met the criteria for adaptation of two of its clinical questions. Systematic literature searches were conducted by the Cochrane STI Group. The tables of evidence and recommendations were made based on the GRADE methodology. The recommendations of the guide were socialized in a meeting of experts with government agencies and patients. Results: An evidence-based Clinical Practice Guidelines for the management of dyspepsia was developed for the Colombian context. Conclusions: The opportune management of dyspepsia would have an impact of the disease in Colombia. © 2015 Asociaciones Colombianas de Gastroenterología, Endoscopia digestiva, Coloproctología y Hepatología.

Objective: To provide an evidence-based clinical practice guideline for the screening of colon and rectal cancer for patients, caregivers, administrative and government bodies at all levels of care in Colombia. Materials and Methods: This guide was developed by a multidisciplinary team with the support of the Colombian Association of Gastroenterology, Cochrane STI Group and Clinical Research Institute of the Universidad Nacional de Colombia. Relevant clinical questions were developed and the search for national and international guidelines in databases was performed. Existing guidelines were evaluated for quality and applicability. None of the guidelines met the criteria for adaptation, so the group decided to develop a de novo guideline. Systematic literature searches were conducted by the Cochrane Group. The tables of evidence and recommendations were made based on the GRADE methodology. The recommendations of the guide were socialized in a meeting of experts with government agencies and patients. Results: An evidence-based Clinical Practice Guidelines for the screening of colorectal cancer was developed for the Colombian context. Conclusions: The opportune detection of colon cancer would have an impact of the disease in Colombia. © 2015 Asociaciones Colombianas de Gastroenterología, Endoscopia digestiva, Coloproctología y Hepatología.

Excessive signaling via the Notch1 receptor inhibits apoptosis in T lymphocytes. Since several antiapoptotic proteins are cleaved by caspases during cell death, we investigated whether Notch1 was a caspase substrate. Results demonstrate that the intracellular domain of Notch1 (NICD) is cleaved into six fragments during apoptosis in Jurkat cells or peripheral T lymphocytes. Notch1 cleavage is prevented by the caspase inhibitors DEVD-fmk and VEID-fmk or by Bcl-2 expression. Caspase-3 and caspase-6 cleave the NICD into six fragments using sites located within the NF-kappaB binding domain, the ankyrin repeats and the transactivation domain. Notch1 cleavage correlates with the loss of HES-1 expression in apoptotic T cells. Notch1 fragments cannot inhibit activation-induced cell death in a T-cell hybridoma, confirming the abrogation of Notch1 antiapoptotic activity by caspases. The ability of the NICD but not the fragments to antagonize Nur77 activity supports a role for this factor in Notch1 antiapoptotic function.