Somatic non-cancerous overgrowth syndrome of obscure molecular etiology: what are the causes and options?

Journal of Molecular Medicine -     

Selectins and selectin ligands in extravasation of cancer cells and organ selectivity of metastasis

Metastatic spreading is a dreadful complication of neoplastic diseases that is responsible for most deaths due to cancer. It consists in the formation of secondary neoplasms from cancer cells that have detached from the primary site. The formation of these secondary sites is not random and several clinical observations indicate that the metastatic colonization exhibits organ selectivity. This organ tropism relies mostly on the complementary adhesive interactions between the cancer cells and their microenvironment. In particular, several lines of evidence suggest that the organ selectivity of colon cancer cells for the liver involves the binding of the circulating cancer cells to endothelial E-selectin. The aim of this review is to make an integrative up-date of the mechanisms that govern the organ selectivity of the metastatic process focusing more especially on the role of selectins and selectin ligands.     

A fluorescent reporter of caspase activity for live imaging

There is a growing interest in the mechanisms that control the apoptosis cascade during development and adult life. To investigate the regulatory events that trigger apoptosis in whole tissues, we have devised a genetically encoded caspase sensor that can be detected in live and fixed tissue by standard confocal microscopy. The sensor comprises two fluorophores, mRFP, monomeric red fluorescent protein (mRFP) and enhanced green fluorescent protein (eGFP), that are linked by an efficient and specific caspase-sensitive site. Upon caspase activation, the sensor is cleaved and eGFP translocates to the nucleus, leaving mRFP at membranes. This is detected before other markers of apoptosis, including anti–cleaved caspase 3 immunoreactivity. Moreover, the sensor does not perturb normal developmental apoptosis and is specific, as cleavage does not occur in Drosophila embryos that are unable to activate the apoptotic cascade. Importantly, dying cells can be recognized in live embryos, thus opening the way for in vivo imaging. As expected from the high conservation of caspases, it is also cleaved in dying cells of chick embryos. It is therefore likely to be generally useful to track the spatiotemporal pattern of caspase activity in a variety of species.     

Low-concentration methylene blue maintains energy production and strongly improves survival of Leigh syndrome French Canadian skin fibroblasts

Leigh syndrome French Canadian (LSFC) is a recessive disease caused by mutations in the LRPPRC gene (leucine-rich pentatricopeptide repeat containing protein). These mutations induce a cytochrome c oxidase (COX) deficiency resulting in episodes of acute acidotic crisis that will often lead to death. There is no effective treatment. Methylene blue (MB) is a redox dye that increases COX content and activity in vitro and in vivo suggesting that MB could prevent and treat LSFC. In this study, the protective effect of low-concentration MB was tested on two LSFC cell lines, including LSFC-F1, homozygous for the mutation A354V, and LSFC-F2 a compound heterozygous for the mutations A354V and C12775STOP. MB effect on metabolic activity was assessed on both LSFC cells in stable and acidotic conditions. For LSFC-F1, results showed that metabolic activity drastically decline after 96 hours in both conditions but not LSFC-F2 and normal cells. MB completely prevents the decrease of metabolic activity in LSFC-F1. Intracellular ATP content was also measured in both culture media. After 96 hours in acidotic medium, ATP content was almost completely depleted for both LSFC cells. Interestingly, MB completely restores ATP content in LSFC-F1 and LSFC-F2 cells. Finally, MB strongly improves the survival of both LSFC cells.     

Freeze lesion-induced focal cortical dysplasia predisposes to atypical hyperthermic seizures in the immature rat

Summary: Purpose: To determine the effects of focal cortical dysplasia on the behavioral and electrographic features of hyperthermia‐induced seizures (HSs) in rats. Methods: A right sensorimotor cortex freeze lesion was induced in postnatal day 1 (P1) rat pups, and HSs were provoked at P10 under continuous monitoring of core temperature; EEGs were recorded from the right amygdala during and after hyperthermia. Controls included both sham‐operated at P1 and naïve rats. Results: HSs began with jaw myoclonus, followed by hindlimb clonus and generalized convulsions (GCs), and terminated by a period of posthyperthermia depression. The threshold temperature and latency of jaw myoclonus were similar across the groups. However, both the threshold temperature and latency of GCs were significantly lower in lesioned pups than in controls (40.5 ± 0.5°C, n = 24, vs. 42.0 ± 0.2°C, n = 21; p < 0.001; 6.7 ± 0.6 min, n = 20, vs. 8.4 ± 0.6 min, n = 22; p < 0.05). In lesioned pups, the threshold and latencies for jaw myoclonus and hindlimb clonus were similar, whereas in controls, the progression from one to the other was marked by significant differences in both parameters. Posthyperthermia depression was longer in lesioned (13.3 ± 1.2 min, n = 21) than in control (8.0 ± 0.8 min, n = 20; p < 0.0001) pups. Ictal EEG activity was recorded during both behavioral seizures and posthyperthermia depression. Conclusions: An HS in rats with a localized freeze lesion results in lower threshold GC and prolonged ictal manifestations, thus supporting a pathophysiologic link between focal cortical dysplasia and atypical febrile seizures, conditions that have a high prevalence in children with mesial temporal lobe epilepsy.     

Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis

Protection against deadly pathogens requires the production of high-affinity antibodies by B cells, which are generated in germinal centers (GCs). Alteration of the GC developmental program is common in many B cell malignancies. Identification of regulators of the GC response is crucial to develop targeted therapies for GC B cell dysfunctions, including lymphomas. The histone H3 lysine 27 methyltransferase enhancer of zeste homolog 2 (EZH2) is highly expressed in GC B cells and is often constitutively activated in GC-derived non-Hodgkin lymphomas (NHLs). The function of EZH2 in GC B cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells caused profound impairment of GC responses, memory B cell formation, and humoral immunity. EZH2 protected GC B cells against activation-induced cytidine deaminase (AID) mutagenesis, facilitated cell cycle progression, and silenced plasma cell determinant and tumor suppressor B-lymphocyte–induced maturation protein 1 (BLIMP1). EZH2 inhibition in NHL cells induced BLIMP1, which impaired tumor growth. In conclusion, EZH2 sustains AID function and prevents terminal differentiation of GC B cells, which allows antibody diversification and affinity maturation. Dysregulation of the GC reaction by constitutively active EZH2 facilitates lymphomagenesis and identifies EZH2 as a possible therapeutic target in NHL and other GC-derived B cell diseases.     

Results in the elderly with locally advanced rectal cancer from the ACCOR12/PRODIGE 2 phase III trial: Tolerance and efficacy

Background

Rectal cancer predominantly affects the elderly. Unfortunately, this age category is under-represented in clinical trials because clinicians are loath to include patients with a high risk of comorbidity.

Patients and methods

An exploratory analysis of the ACCORD12/PRODIGE 2 phase III trial was carried out to retrospectively compare the benefit of neoadjuvant chemotherapy between the elderly (?70 years; n = 142) and younger patients (<70 years; n = 442), this analysis was not preplanned in the study protocol. Patients with histologically confirmed resectable stage T3 or T4 rectal adenocarcinoma were eligible with an age limit of 80 years.

Results

Overall, the two age categories did not statistically differ in terms of patient’s clinical and tumor baseline characteristics. Preoperative chemoradiotherapy leads to more severe grade 3/4 toxicities (25.6% vs. 15.8%, p = 0.01) and more permanent stomas (33.3% vs. 22.8%, p = 0.014) in elderly patients who were less often operated on than younger patients (95.8% vs. 99.0%, p = 0.008). The relative number of interventions per surgery type (p = 0.18), treatment efficacy in terms of R0 resection rate (88.6% vs. 90.6%; p = 0.54) and complete pathological response (14.7% vs. 16.9%; p = 0.55) were nearly identical between the two categories.

Conclusion

Altogether these results warrant the development of specific optimal therapeutic strategies for the elderly.