The serine-threonine kinase p90RSK is a new target of enzastaurin in follicular lymphoma cells.

BACKGROUND AND PURPOSE: Follicular lymphoma is the second most common non-Hodgkin's lymphoma and, despite the introduction of rituximab for its treatment, this disease is still considered incurable. Besides genetic alterations involving Bcl-2, Bcl-6 or c-Myc, follicular lymphoma cells often display altered B-cell receptor signalling pathways including overactive PKC and PI3K/Akt systems. EXPERIMENTAL APPROACH: The effect of enzastaurin, an inhibitor of PKC, was evaluated both in vitro on follicular lymphoma cell lines and in vivo on a xenograft murine model. Using pharmacological inhibitors and siRNA transfection, we determined the different signalling pathways after enzastaurin treatment. KEY RESULTS: Enzastaurin inhibited the serine-threonine kinase p90RSK which has downstream effects on GSK3ß. Bad and p70S6K. These signalling proteins control follicular lymphoma cell survival and apoptosis; which accounted for the inhibition by enzastaurin of cell survival and its induction of apoptosis of follicular lymphoma cell lines in vitro. Importantly, these results were replicated in vivo where enzastaurin inhibited the growth of follicular lymphoma xenografts in mice. CONCLUSIONS AND IMPLICATIONS: The targeting of p90RSK by enzastaurin represents a new therapeutic option for the treatment of follicular lymphoma.

Anti-tumor activity of obinutuzumab and rituximab in a follicular lymphoma 3D model.

Follicular lymphomas (FLs) account for 35-40% of all adult lymphomas. Treatment typically involves chemotherapy combined with the anti-CD20 monoclonal antibody (MAb) rituximab (RTX). The development of the type II anti-CD20 MAb obinutuzumab (GA101) aims to further improve treatment. Here, using FL cells we show that RTX and GA101 display a similar activity on RL cells cultured in 2D. However, 2D culture cannot mimic tumor spatial organization and conventional 2D models may not reflect the effects of antibodies as they occur in vivo. Thus, we created a non-Hodgkin's lymphoma (NHL) 3D culture system, termed multicellular aggregates of lymphoma cells (MALC), and used it to compare RTX and GA101 activity. Our results show that both antibodies display greater activity towards FL cells in 3D culture compared with 2D culture. Moreover, we observed that in the 3D model GA101 was more effective than RTX both in inhibiting MALC growth through induction of (lysosomal) cell death and senescence and in inhibiting intracellular signaling pathways, such as mammalian target of rapamycin, Akt, PLCgamma (Phospholipase C gamma) and Syk. Altogether, our study demonstrates that spatial organization strongly influences the response to antibody treatment, supporting the use of 3D models for the testing of therapeutic agents in NHL.

[Clinical characteristics and follow-up of patients attending a hospital hypertension clinic. 10-year experience]. / Características clínicas y evolutivas de los pacientes asistidos en una consulta especializada de hipertensión arterial. Experiencia de 10 años.

OBJECTIVE: To analyze the characteristics and control of hypertensive patients visited in a hospital hypertension clinic, dependent of the internal medicine department. METHODS: The study included 597 hypertensive patients, mean age 51.9 years (range 14-85), visited consecutively during the period 1989-1998. We applied the following initial protocol: Usual and orientated HBP anamnesis and physical examination, routine blood and urine test, standard electrocardiography and abdominal echocardiography. If necessary, we indicated other test or special explorations. After every visit, the data were stored into an electronic database, which we analyzed retrospectively to obtain the data of this study. RESULTS: Initial and final BP were: systolic BP 154 +/- 25 vs 141 +/- 21 mmHg, Dif. -12.9 (95% CI -14.8 a -11.0), and diastolic BP 96 +/- 12 vs 88 +/- 19 mmHg, Dif. -7.6 (95% CI -8.6 a -6.6). Four hundred and five patients (79.5%) presented I-II OMS stage and 121 (20.2%) III stage. One hundred and seventy-four cardiovascular events were registered. Hypercholesterolemia and obesity were present in 32% of the patients. Seventy-four (10.7%) had secondary HBP. ECA inhibitors were the antihypertensive drugs more used, either associated (58.9%) or as monotherapy (37%). Nine hundred patients (31.8%) presented optimal BP control (< 140/90 mmHg), and 27 (4.5%) refractory HBP. Weight and laboratory values (but uric acid) did not change significantly during the follow-up period. CONCLUSIONS: The patients showed a high prevalence of severe cardiovascular events, and associated risk factors. The 10% presented secondary HBP. About 31% of the patients reached optimal BP control.

[Immunogammagraphy with anti-CEA and anti-TAG-72 monoclonal antibodies in the diagnosis of colorectal carcinoma]. / Inmunogammagrafía con anticuerpos monoclonales anti-CEA y anti-TAG-72 en el diagnóstico del carcinoma colorrectal.

BACKGROUND: The purpose of nuclear medicine in the evaluation of colorectal carcinoma is to complete the current diagnostic protocol, by means of monoclonal antibodies (MoAb) against tumoral antigens labelled with radioactive isotopes and performing an immunoscintigraphy. PATIENTS AND METHODS: Immunoscintigraphies have been performed to 143 patients with colorectal carcinoma. Group I: antiCEA MoAb 99mTc-BW 431/26 (72 patients with 74 lesions, 48 primary tumors and 26 recurrences); group II: antiTAT-72 MoAb 111In-CYT-103 (71 patients with 75 lesions, 28 primary tumors and 47 recurrences). All positive images, not corresponding to physiological distribution of MoAb, have been considered as pathological. RESULTS: The sensitivity in the diagnosis of primary tumors in group I was worse than in group II (54.2% vs 66.7%). If rectum tumors were excluded, the sensitivity increased to 80% and 85.7%, respectively. In the suspicion of recurrences, if only lesions confirmed at surgery were considered, the sensitivity was 75% in group I and 89.7% in group II. The immunoscintigraphy has been the only technique able to diagnose recurrences in 4/23 cases from group I and 14/32 from group II. In liver, considering as metastases only hot images, the sensitivity is very low in group I (44.4%) and null in group II. No relationship has been found between tumour markers levels and the immunoscintigraphic result. CONCLUSIONS: Immunoscintigraphy is useful in patients with colorectal carcinoma, especially in the case of recurrences and it is a complementary technique to other diagnostic procedures.