Role of IL-2 in rat fetal thymocyte development

Early during rat thymus ontogeny, an important proportion of thymocytes expresses IL-2R and contains IL-2 mRNA. To investigate the role of the IL-2-IL-2R complex in rat T cell maturation, we supplied either recombinant rat IL-2 or blocking anti-CD25 mAb to rat fetal thymus organ cultures (FTOC) under several experimental conditions. The IL-2 treatment initially stimulated the growth of thymocytes and, as a result, induced T cell differentiation, but the continuous addition of IL-2 to rat FTOC, as well as the anti-CD25 administration, resulted in cell number decrease and inhibition of thymocyte maturation. These results indicate that immature rat thymocytes bear functional high- affinity IL-2R and that IL-2 promotes T cell differentiation as a consequence of its capacity to stimulate cell proliferation. Modifications in TCR alpha beta repertoire and increased numbers of NKR- P1+ cells, largely NK cells, were also observed in IL-2-treated FTOC. Furthermore, IL-2-responsiveness of different thymocyte subsets changed throughout thymic ontogeny. Immature CD4-CD8-cells responded to IL-2 in two stages, early in thymus development and around birth, in correlation with the maturation of two distinct waves of thymic cell progenitors. Mature CD8+ thymocytes maximally responded to IL-2 around birth, supporting a role for IL-2 in the increased proliferation of mature thymocytes observed in vivo in the perinatal period. Taken together, these findings support a role for IL-2 in rat T cell development.      

Preoperative detection of gastrointestinal neuroendocrine tumors using endoscopic ultrasonography.

OBJECTIVE: Almost 30% of gastroenteropancreatic neuroendocrine tumors (GEPET) escape preoperative identification using standard imaging techniques. The goal of this retrospective study is to present our cumulative experience in the assessment of GEPET by preoperative endoscopic ultrasonography (EUS), and to compare it with a literature review. PATIENTS AND METHODS: Thirty-seven patients with suspected specific hormonal syndromes were sequentially examined with US, CT, MRI, angiography, OctreoScan, and radial and sectorial EUS. Sixteen were males (43%) and 21 were females (57%), with a mean age of 61 years (interval: 40-84 a). Of all 37 patients, 27 had 19 endocrine tumors in the pancreas and 14 tumors in their gastrointestinal tract. No tumors were demonstrated in 10 patients, hence they were used as a control group. Of all 37 patients, 24 were operated on or had histological samples collected, with the presence of 26 GEPET (10 carcinoids) being confirmed in 22 patients. RESULTS: EUS sensitivity and diagnostic accuracy were 81% and 78%. Specificity was 80%. All these values were similar to the mean values obtained from the literature review. Three pancreatic rumors smaller than or equal to 1 cm (insulinomas) were detected, which had escaped diagnosis with previous US, CT, and MRI studies. An echoendoscopic examination of the pancreas could not be completed in two cases (5%), a pancreas carcinoid and an already gastrectomized double pancreatic gastrinoma. CONCLUSION: EUS is a good preoperative technique for GEPET detection, and may likely be superior to other imaging techniques in the assessment of small tumors. The usefulness of EUS as a primary exploration after US or HCT has been posited for tumor diagnosis and localization before surgery.     

EUS-guided mucosectomy for gastrointestinal cancer.

INTRODUCTION: the only way of improving prognosis and survival in gastrointestinal cancer is early diagnosis, with intramucosal localization as confirmed by endoscopic ultrasonography (EUS) or 20-MHz miniprobes (MPs) (T1) being most appropriate. Endoscopic mucosal resection (EMR) has proven effective in the treatment of this sort of lesions. PATIENTS AND METHOD: in a group (18 cases) with 15 cases of superficial gastrointestinal cancer and 3 cases of severe gastric dysplasia, 9 cases (3 esophageal, 4 gastric, 2 rectal) underwent a classic EMR following EUS or a 7.5- and 20-MHz miniprobe exploration. RESULTS: ultrasonographic studies showed a T1 in all but one esophageal case (Tis), and in both gastric dysplasias, with no changed layer structure being demonstrated in the latter (T0). No complications arose with classic EMR, and all 9 patients are alive and free from local or metastatic recurrence, except for one esophageal case, which recurred distally to the esophageal lesion (metachronous). CONCLUSIONS: echoendoscopically-assisted EMR is a safe, effective technique in the endoscopic management of superficial gastrointestinal (esophageal, gastric, colorectal) cancer. Recurrence most likely depends upon cancer multiplicity.     

Bone morphogenetic protein-2/4 signalling pathway components are expressed in the human thymus and inhibit early T-cell development

T-cell differentiation is driven by a complex network of signals mainly derived from the thymic epithelium. In this study we demonstrate in the human thymus that cortical epithelial cells produce bone morphogenetic protein 2 (BMP2) and BMP4 and that both thymocytes and thymic epithelium express all the molecular machinery required for a response to these proteins. BMP receptors, BMPRIA and BMPRII, are mainly expressed by cortical thymocytes while BMPRIB is expressed in the majority of the human thymocytes. Some thymic epithelial cells from cortical and medullary areas express BMP receptors, being also cell targets for in vivo BMP2/4 signalling. The treatment with BMP4 of chimeric human-mouse fetal thymic organ cultures seeded with CD34+ human thymic progenitors results in reduced cell recovery and inhibition of the differentiation of human thymocytes from CD4- CD8- to CD4+ CD8+ cell stages. These results support a role for BMP2/4 signalling in human T-cell differentiation.     

The choroid plexus stroma constitutes a sanctuary for paediatric B-cell precursor acute lymphoblastic leukaemia in the central nervous system

Despite current central nervous system-directed therapies for childhood B-cell precursor acute lymphoblastic leukaemia, relapse at this anatomical site still remains a challenging issue. Few reports have addressed the study of the specific cellular microenvironments which can promote the survival, quiescence, and therefore chemoresistance of B-cell precursor acute lymphoblastic leukaemia cells in the central nervous system. Herein, we showed by immunofluorescence and electron microscopy that in xenotransplanted mice, leukaemic cells infiltrate the connective tissue stroma of the choroid plexus, the brain structure responsible for the production of cerebrospinal fluid. The ultrastructural study also showed that leukaemia cells are able to migrate through blood vessels located in the choroid plexus stroma. In short-term co-cultures, leukaemic cells established strong interactions with human choroid plexus fibroblasts, mediated by an increased expression of ITGA4 (VLA-4)/ITGAL (LFA-1) and their ligands VCAM1/ICAM1. Upon contact with leukaemia cells, human choroid plexus fibroblasts acquired a cancer-associated fibroblast phenotype, with an increased expression of α-SMA and vimentin as well as pro-inflammatory factors. Human choroid plexus fibroblasts also have the capacity to reduce the proliferative index of leukaemic blasts and promote their survival and chemoresistance to methotrexate and cytarabine. The inhibition of VLA-4/VCAM-1 interactions using anti-VLA-4 antibodies, and the blockade of Notch signalling pathway by using a γ-secretase inhibitor partially restored chemotherapy sensitivity of leukaemia cells. We propose that the choroid plexus stroma constitutes a sanctuary for B-cell precursor acute lymphoblastic leukaemia cells in the central nervous system. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.     

Revisiting the mammographic follow-up of BI-RADS category 3 lesions

OBJECTIVE: Using data collected for one series during 1987-1989 and data collected for another series during 1996, we sought to compare the frequency of and positive predictive value for carcinoma of the breast in nonpalpable, probably benign lesions that had been detected on and followed up with mammography. MATERIALS AND METHODS: During 1996, mammography was performed in 18,435 women of whom 544 (3.0%) had lesions assigned to Breast Imaging Reporting and Data System (BI-RADS) category 3 for nonpalpable, probably benign lesions. The lesions in the women were assessed as BI-RADS category 3 after the patients had undergone a diagnostic study that included additional imaging, sonography, and a focused physical examination. Patients with BI-RADS category 3 lesions were recommended for mammographic surveillance. A minimum of 2 years of follow-up data was available for 511 patients, our study population. We compared the findings for our study population with those of the previous study. RESULTS: Ninety-seven percent of the follow-up mammograms showed stability or regression of the BI-RADS category 3 lesions. Fourteen patients (3%) had nonpalpable interval progression revealed on mammography and underwent biopsy. The breast cancer detection rate in category 3 lesions among the study population was 0.4% (2/511), which was 14% of the patients who had undergone biopsies because of interval progression of the lesions. The pathologic stage of the cancers in these two patients was T1b N0. CONCLUSION: Compared with the findings from the 1987-1989 study, the frequency of BI-RADS category 3 lesions has remained stable; patient compliance for follow-up has increased; and the positive predictive value of category 3 lesions for cancer has decreased from 1.7% to 0.4% (p = 0.04).     

Diacylglycerol kinase alpha activity promotes survival of CD4+ 8+ double positive cells during thymocyte development

The diacylglycerol kinases (DGK) form a family of isoenzymes that catalyse the conversion of diacylglycerol (DAG) to phosphatidic acid (PA), both powerful second messengers in the cell. DGKalpha is expressed in brain, peripheral T cells and thymocytes and has been shown to translocate to the nuclear matrix upon T-cell receptor (TCR) engagement. Here, we show that high level expression of DGKalpha is induced following a signal transmitted through the pre-TCR and the protein tyrosine kinase, lck. Activity of DGKalpha contributes to survival in CD4+ 8+ (DP) thymocytes as pharmacological inhibition of DGK activity results in death of this cell population both in cell suspension and thymic explants. DGKalpha promotes survival in these thymocytes through a Bcl-regulated pathway. A consequence of inhibition of DGKalpha is the specific down-regulation of Bcl-xl, whereas in transgenic mice that over-express Bcl-2, death induced by the inhibitor is partially blocked. Thus we report a novel activity of DGKalpha in survival of thymocytes immediately after entry into the DP stage in development.