Lack of L-selectin expression by cells transferring diabetes in NOD mice: insights into the mechanisms involved in diabetes prevention by Mel-14 antibody treatment

The process of mononuclear cell extravasation from the blood into the islets of Langerhans in nonobese diabetic (NOD) mice is dependent on the expression of a set of molecules, most of which remain to be defined. The observation that vascular addressins are expressed in inflamed islets raises the issue of the involvement of one of their ligands, L-selectin, in the pathogenesis of autoimmune diabetes. Treatment of NOD females with Mel-14, an antibody specific for L-selectin, reduced the spontaneous development of both insulitis and diabetes. Pretreatment of diabetic donors with Mel-14 decreased the capacity of their splenocytes to transfer the disease. However, the treatment of recipients had no effect on the transfer of diabetes by untreated diabetogenic splenocytes. To reconcile these apparently conflicting results, we fractionated spleen T cells from diabetic mice according to L-selectin expression. Diabetogenic cells were found only in the L-selectin subpopulation. Thus, diabetogenic cells in adult mice share phenotypic characteristics with activated/memory cells, and enter the pancreas using L-selectin-independent migratory pathways.     

Functional proteomics mapping of a human signaling pathway

Access to the human genome facilitates extensive functional proteomics studies. Here, we present an integrated approach combining large-scale protein interaction mapping, exploration of the interaction network, and cellular functional assays performed on newly identified proteins involved in a human signaling pathway. As a proof of principle, we studied the Smad signaling system, which is regulated by members of the transforming growth factor beta (TGFbeta) superfamily. We used two-hybrid screening to map Smad signaling protein-protein interactions and to establish a network of 755 interactions, involving 591 proteins, 179 of which were poorly or not annotated. The exploration of such complex interaction databases is improved by the use of PIMRider, a dedicated navigation tool accessible through the Web. The biological meaning of this network is illustrated by the presence of 18 known Smad-associated proteins. Functional assays performed in mammalian cells including siRNA knock-down experiments identified eight novel proteins involved in Smad signaling, thus validating this integrated functional proteomics approach.     

Strain-Dependent Migration of CD4 and CD8 Lymphocyte Subsets to Lymph Nodes in NOD (Nonobese Diabetic) and Control Mice

Subpopulations of lymphoid cells were compared with respect to their ability to migrate into peripheral lymphoid organs of nonobese diabetic (NOD) mice and various strains of control mice. In short-term, in vivo homing studies, no major differences in the pattern of homing of B and T cells were observed among all mouse strains studied. On the other hand, CD4 cells localized consistently more efficiently than CD8 cells in both PP and LN of adult NOD and BALB/c mice, whereas both populations migrated roughly equivalently in LN of adult DBA/2, CBA, and C57BL/6 mice. No age-dependent differences in the homing of CD4 and CD8 cells were observed in BALB/c mice. On the contrary, in 2-week-old NOD mice, CD4 and CD8 cells migrated equally well. The preferential entry of CD4 cells in adult NOD and BALB/c did not result from increased blood transit time of CD8 cells. On the other hand, the preferential migration of CD8 cells was observed in the liver, whereas the two T-cell subsets migrated equally well in the lungs. The differences in the homing characteristics of CD4 and CD8 cells among NOD, BALB/c, and C57BL/6 mice were not related to modifications in the level of expression of adhesion molecules such as MEL-14, LFA-1, and Pgp-1.     

Congenital posterior cervical spine malformation due to biallelic c.240‐4T>G RIPPLY2 variant: A discrete entity

The clinical and radiological spectrum of spondylocostal dysostosis syndromes encompasses distinctive costo‐vertebral anomalies. RIPPLY2 biallelic pathogenic variants were described in two distinct cervical spine malformation syndromes: Klippel–Feil syndrome and posterior cervical spine malformation. RIPPLY2 is involved in the determination of rostro‐caudal polarity and somite patterning during development. To date, only four cases have been reported. The current report aims at further delineating the posterior malformation in three new patients. Three patients from two unrelated families underwent clinical and radiological examination through X‐ray, 3D computed tomography and brain magnetic resonance imaging. After informed consent was obtained, family‐based whole exome sequencing (WES) was performed. Complex vertebral segmentation defects in the cervico‐thoracic spine were observed in all patients. WES led to the identification of the homozygous splicing variant c.240‐4T>G in all subjects. This variant is predicted to result in aberrant splicing of Exon 4. The current report highlights a subtype of cervical spine malformation with major atlo‐axoidal malformation compromising spinal cord integrity. This distinctive mutation‐specific pattern of malformation differs from Klippel–Feil syndrome and broadens the current classification, defining a sub‐type of RIPPLY2‐related skeletal disorder. Of note, the phenotype of one patient overlaps with oculo‐auriculo‐vertebral spectrum disorder.     

Sleep deprivation effects on growth factor expression in neonatal rats: a potential role for BDNF in the mediation of delta power

The sleeping brain differs from the waking brain in its electrophysiological and molecular properties, including the expression of growth factors and immediate early genes (IEG). Sleep architecture and homeostatic regulation of sleep in neonates is distinct from that of adults. Hence, the present study addressed the question whether the unique homeostatic response to sleep deprivation in neonates is reflected in mRNA expression of the IEG cFos, brain-derived nerve growth factor (BDNF), and basic fibroblast growth factor (FGF2) in the cortex. As sleep deprivation is stressful to developing rats, we also investigated whether the increased levels of corticosterone would affect the expression of growth factors in the hippocampus, known to be sensitive to glucocorticoid levels. At postnatal days 16, 20, and 24, rats were subjected to sleep deprivation, maternal separation without sleep deprivation, sleep deprivation with 2 h recovery sleep, or no intervention. mRNA expression was quantified in the cortex and hippocampus. cFos was increased after sleep deprivation and was similar to control level after 2 h recovery sleep irrespective of age or brain region. BDNF was increased by sleep deprivation in the cortex at P20 and P24 and only at P24 in the hippocampus. FGF2 increased during recovery sleep at all ages in both brain regions. We conclude that cortical BDNF expression reflects the onset of adult sleep-homeostatic response, whereas the profile of expression of both growth factors suggests a trophic effect of mild sleep deprivation.     

Intravenous treatment with liposome-encapsulated dichloromethylene bisphosphonate (C12MBP)suppresses nitric oxide production and reduces genetic resistance to Marek's disease

In this study the functional effectiveness of in vivo macrophage depletion using liposome-encapsulateddichloromethylene bisphosphonate (C12MBP) was examined in the chicken. The main target organs forsystemic liposome-encapsulated C12MBP treatment are the spleen and the liver. Intravenous treatment withC12MBP of B²¹/B²¹ chickens, genetically resistant to Marek's disease (MD), before challenge with the very virulent strain RB-lB, increased viral load in the blood and spleen after the first week and up to 6 weeks postinfection. In addition, C12MBP treatment dramatically increased tumour incidence and tumour load, especially in the spleens and livers of sick animals, but without affecting MD-specific mortality of B²¹/B²¹ cickens infected with RB-1B at 12 days of age. Nitric oxide (NO) is an important effector of the macrophage and has antiviral and antitumoural properties. NO has been shown to be one of the mechanisms triggered in resistance to Marek's disease. Intravenous treatment with Cl2MBP before infection with RB-1B induced a long-lasting decrease in numbers of macrophages and reduction in splenic inducible NO production associated with an absence of nitrate induction in the serum (up to 6 weeks pi). These results do not identify macrophage and NO production as major effector components in genetic resistance to Marek's disease, but underline their roles in limiting viraemia and tumour development in organs such as the spleen and the liver.     

Evolution of health care utilization and expenditure during the year before death in 2015 among people with cancer: French snds-based cohort study

The European Journal of Health Economics - Cancer patients have one of the highest health care expenditures (HCE) at the end of life. However, the growth of HCE at the end of life remains poorly...     

Eribulin combined with radiation therapy in a young patient re-irradiated for a new lesion of breast cancer

Eribulin is widely used in the treatment of metastatic breast cancer, with a manageable toxicity profile. This aggressive disease often requires systemic and local treatments, comprising surgery or radiotherapy. However, eribulin is usually discontinued during radiation therapy due to the lack of data concerning the safety of this combination, especially in the setting of repeat locoregional radiation therapy. Our patient was diagnosed with ER positive invasive ductal carcinoma of the left breast initially treated by surgery, radiation therapy, chemotherapy, and hormone therapy. She then received various lines of chemotherapy for multiple triple-negative relapses in the left axillary region. Since October 2020, she has been treated by eribulin. In order to improve local control, it was decided to add local radiation therapy to the region of recurrence in addition to systemic therapy. She underwent radiation therapy concomitantly with eribulin from February to March 2021. Treatment was very well tolerated, and no acute toxicity was reported. This is the first published case of repeat locoregional radiation therapy in combination with eribulin.