Antitumor efficacy and safety of unedited autologous CD5.CAR T cells in relapsed/refractory mature T-cell lymphomas.

ABSTRACT: Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor (CAR) T-cell platforms to treat T-cell malignancies often requires additional gene modifications to overcome fratricide because of shared T-cell antigens on normal and malignant T cells. We developed a CD5-directed CAR that produces minimal fratricide by downmodulating CD5 protein levels in transduced T cells while retaining strong cytotoxicity against CD5+ malignant cells. In our first-in-human phase 1 study (NCT0308190), second-generation autologous CD5.CAR T cells were manufactured from patients with r/r T-cell malignancies. Here, we report safety and efficacy data from a cohort of patients with mature T-cell lymphoma (TCL). Among the 17 patients with TCL enrolled, CD5 CAR T cells were successfully manufactured for 13 out of 14 attempted lines (93%) and administered to 9 (69%) patients. The overall response rate (complete remission or partial response) was 44%, with complete responses observed in 2 patients. The most common grade 3 or higher adverse events were cytopenias. No grade 3 or higher cytokine release syndrome or neurologic events occurred. Two patients died during the immediate toxicity evaluation period due to rapidly progressive disease. These results demonstrated that CD5.CAR T cells are safe and can induce clinical responses in patients with r/r CD5-expressing TCLs without eliminating endogenous T cells or increasing infectious complications. More patients and longer follow-up are needed for validation. This trial was registered at www.clinicaltrials.gov as #NCT0308190.

Caracterización de la sífilis congénita y gestacional en Caldas, Colombia / Characterization of congenital and gestational syphilis in Caldas (Colombia)

Objetivo: caracterizar el comportamiento de la sífilis congénita y gestacional en el departamento de Caldas durante el periodo 2009-2013 según las características socio demográficas y de la atención en salud del binomio madre-hijo con sífilis. Materiales y métodos: se realizó un estudio descriptivo de 71 casos de sífilis congénita y 316 casos de sífilis gestacional, reportados a través del sistema de vigilancia epidemiológica SIVIGILA. Resultados: el comportamiento de la sífilis congénita y gestacional en este periodo, indica un descenso de los casos en los no afiliados e incremento de los mismos en el régimen contributivo y subsidiado. Las gestantes con sífilis en edades entre 16 a 35 años, afiliadas al régimen subsidiado, residentes en las cabeceras municipales y no hospitalizadas, presentaron una fuerte correspondencia con la condicional final viva.Los neonatos con sífilis hospitalizados, con una condición final de vivos presentaron una fuerte correspondencia a pertenecer al régimen subsidiado. Conclusiones: la población con mayor número de casos registrados de sífilis gestacional en el departamento de Caldas en este estudio, corresponde a las gestantes del régimen subsidiado que residen en las cabeceras municipales atendidas en el segundo y tercer nivel de servicios de salud. El régimen subsidiado en salud diagnostica la sífilis gestacional durante los controles prenatales; mientras que, el régimen contributivo diagnostica sífilis gestacional en el parto. Independiente del régimen en salud las parejas de gestantes con sífilis no acuden a los servicios de salud...(AU)

Objective: to characterize the behavior of gestational and congenital syphilis in the department of Caldas during the 2009-2013 period according to sociodemographic characteristics and health care of mothers and children with syphilis. Materials and Methods: a descriptive study of 71 cases of congenital syphilis and 316 cases of gestational syphilis reported through the surveillance system was conducted SIVIGILA.Results: the behavior of congenital syphilis and gestational during the study, indicating a decline in cases unaffiliated and increase them in the contributory scheme and subsidized. Pregnant women with syphilis diagnosed between the ages of 16-35 years affiliated with the subsidized regime, which reside in the municipalities and were not hospitalized, had a strong correspondence with the final conditional alive. Infants with syphilis who were hospitalized, with a final condition of living showed a strong correspondence to belong to the subsidized regime. Conclusions: the population with the highest number of reported cases of gestational syphilis in the department of Caldas, in the last five years, corresponding to the subsidized pregnant residing in the municipalities with secondary and tertiary health care. The subsidized health regime gestational syphilis diagnosed during prenatal care mainly; however, with a less strong relationship, the tax regime gestational syphilis diagnosed at birth. To this we add, regardless of the health system, which couples of pregnant women with syphilis do not attend health services...(AU)

Integrated Medical Curriculum: Advantages and Disadvantages.

Most curricula for medical education have been integrated horizontally and vertically--vertically between basic and clinical sciences. The Flexnerian curriculum has disappeared to permit integration between basic sciences and clinical sciences, which are taught throughout the curriculum. We have proposed a different form of integration where the horizontal axis represents the defined learning outcomes and the vertical axis represents the teaching of the sciences throughout the courses. We believe that a mere integration of basic and clinical sciences is not enough because it is necessary to emphasize the importance of humanism as well as health population sciences in medicine. It is necessary to integrate basic and clinical sciences, humanism, and health population in the vertical axis, not only in the early years but also throughout the curriculum, presupposing the use of active teaching methods based on problems or cases in small groups.

Genetic damage in patients with chronic kidney disease, peritoneal dialysis and haemodialysis: a comparative study.

Patients with chronic kidney disease (CKD) have signs of genomic instability and, as a consequence, extensive genetic damage, possibly due to accumulation of uraemic toxins, oxidative stress mediators and other endogenous substances with genotoxic properties. We explored factors associated with the presence and background levels of genetic damage in CKD. A cross-sectional study was performed in 91 CKD patients including pre-dialysis (CKD patients; n = 23) and patients undergoing peritoneal dialysis (PD; n = 33) or haemodialysis (HD; n = 35) and with 61 healthy subjects, divided into two subgroups with the older group being in the age range of the patients, serving as controls. Alkaline comet assay and cytokinesis-block micronucleus assay in peripheral blood lymphocytes were used to determine DNA and chromosome damage, respectively, present in CKD. Markers of oxidative stress [malondialdehyde (MDA), advanced glycation end products (AGEs), thiols, advanced oxidation protein products and 8-hydroxy-2'-deoxyguanosine] and markers of inflammation (C-reactive protein, interleukin-6 and tumour necrosis factor alpha) were also measured. Micronucleus (MN) frequency was significantly higher (P < 0.05) in the CKD group (46±4‰) when compared with the older control (oC) group (27.7±14). A significant increase in MN frequency (P < 0.05) was also seen in PD patients (41.9±14‰) versus the oC group. There was no statistically significant difference for the HD group (29.7±15.6‰; P = NS) versus the oC group. Comet assay data showed a significant increase (P < 0.001) of tail DNA intensity in cells of patients with CKD (15.6±7%) with respect to the total control (TC) group (11±1%). PD patients (14.8±7%) also have a significant increase (P < 0.001) versus the TC group. Again, there was no statistically significant difference for the HD group (12.5±3%) compared with the TC group. Patients with MN values in the upper quartile had increased cholesterol, triglycerides, AGEs and MDA levels and lower albumin levels. Multiple logistic regression analysis showed that male gender, diabetes and treatment modality were independently associated with higher levels of DNA damage. Our results suggest that oxidative stress, diabetes, gender and dialysis modality in CKD patients increased DNA and chromosome damage. To confirm these data, prospective clinical trials need to be performed.

[Renal disease in diabetics. Immunological bases of tubule-interstitial fibrosis and glomeruloesclerosis. Current therapeutic approach]. / Enfermedad renal en el diabético. Bases inmunológicas de la fibrosis tubulointersticial y la glomeruloesclerosis. Enfoque terapéutico actual.

Susceptibility of kidney to become target of the immunological aggression is easily recognizable when we consider the high number of diseases that, with a pathogenesis explained by autoimmunity mechanisms, have the kidney as a target organ. In diabetes mellitus, hyperglycemic state stimulates different molecular factors conditioning tubule-interstitial fibrosis and glomerulosclerosis, among them the most important are: formation of products of advanced glycation; activation of protein kinase C, activation of the angiotensin II and the activation of the nuclear factor kappaB. These factors are closely related to the production of inflammatory cytokines and to the progression of renal damage. This paper reviews the role of these factors in the renal damage of diabetic patients and the effect of some drugs on the progression of the immunological damage.