DNAX accessory molecule‐1 (CD226) promotes human hepatocellular carcinoma cell lysis by Vγ9Vδ2 T cells

Human Vγ9Vδ2 T lymphocytes can be activated by nonpeptidic antigens such as the mevalonate pathway‐derived isopentenyl pyrophosphate or synthetic phosphoantigen such as bromohydrin pyrophosphate. They display a strong cytotoxic activity against several tumor types, including hepatocellular carcinoma (HCC). Little is known about the mechanisms underlying Vγ9Vδ2 T‐cell recognition of tumor cells, but there is strong evidence that activating NK receptors play a role in γδ T‐cell cytotoxicity. In this study, we showed that the two NK receptors DNAX accessory molecule‐1 (DNAM‐1) and CD96 were expressed by Vγ9Vδ2 T cells. The ligands Nectin‐like‐5 specific of both DNAM‐1 and CD96, and also Nectin‐2, an additional ligand of DNAM‐1, were present on all HCC cell lines analyzed. Furthermore, we demonstrated by mAb‐mediated masking experiments that cytotoxicity against HCC cells as well as IFN‐γ production in γδ T cells were dependent on DNAM‐1. Our experiments indicated that Nectin‐like‐5 but not Nectin‐2 was involved in DNAM‐1‐dependent γδ T‐cell functions. We did not reveal a role for CD96 in the killing of HCC cells. Finally, we showed by combined mAb‐mediated blockade that DNAM‐1 and NKG2D could cooperate in the cell lysis of HCC.     

Hypocretin /orexin contributes to the expression of some but not all forms of stress and arousal

Hypocretin/orexin has a well-established role in wakefulness and in the maintenance of arousal. Because stress is associated with arousal, it has been proposed that hypocretin is also involved in stress. However, it is not clear if this is true for all forms of stress. To clarify this issue, we compared four conditions combining high arousal with no or low stress (wakefulness and exploration) or high stress (contextual fear and restraint) in the rat. We looked at Fos expression in hypocretin neurons, hypocretin-1 levels in cerebrospinal fluid and cardiovascular and behavioural changes after pharmacological blockade with the dual hypocretin receptor antagonist, almorexant. Fos expression in hypocretin neurons was highest with wakefulness and exploration, also high with fear but not significant with restraint. Hypocretin-1 levels were consistent with this pattern, although the differences were not as marked. Hypocretin receptor blockade with almorexant reduced the pressor, tachycardic and locomotor responses of wakefulness and exploration as well as the pressor and sympathetic component of the tachycardic response of fear. In contrast, almorexant did not reduce the pressor and tachycardic responses of restraint and nor did it reduce the pressor, tachycardic and locomotor responses of another stressor, i.e. cold exposure. Thus, hypocretin is not involved in all forms of stress. Comparison of the different conditions suggests that, regardless of stress, hypocretin involvement occurs when the arousal associated with the response includes increased attention to environmental cues. When it does, hypocretin will at least contribute to the cardiovascular response. The findings are of clinical relevance to some forms of psychological stress.     

Different functional basal ganglia subcircuits associated with anti-akinetic and dyskinesiogenic effects of antiparkinsonian therapies

Subthalamic nucleus high frequency stimulation (STN-HFS) efficiently alleviates l-DOPA-sensitive parkinsonian motor symptoms, but has no direct beneficial action on l-DOPA-induced dyskinesias (LID). Here, we provide evidence that anti-akinetic STN-HFS or dyskinesiogenic l-DOPA similarly reversed the dopamine lesion-induced increases in gene expression of cytochrome oxidase subunit I (CoI), a metabolic marker of neuronal activity, in the globus pallidus, STN and substantia nigra pars reticulata (SNr) in rats. In contrast, in entopeduncular nucleus (EP), STN-HFS did not modify the lesion-induced increase in CoI mRNA levels, whereas l-DOPA induced a marked decrease versus control. Combining the two treatments did not reveal significant interaction. Interestingly, CoI gene expression in EP but not in SNr was inversely correlated with striatal preprodynorphin mRNA level, a LID marker. This work suggests the existence of two functional basal ganglia subcircuits: the one, including STN and SNr, involved in antiparkinsonian action, and the other, including EP, preferentially involved in LID.     

Microvascular endothelial function in obstructive sleep apnea: Impact of continuous positive airway pressure and mandibular advancement

ObjectivesEndothelial dysfunction has been proposed as a potential mechanism implicated in the pathogenesis of cardiovascular complications of obstructive sleep apnea syndrome (OSAS). This study aimed to evaluate the microvascular endothelial function (MVEV) in OSAS and the impact on MVEF of 2 months of treatment with continuous positive airway pressure (CPAP) and mandibular advancement device (MAD).MethodsMicrovascular reactivity was assessed using laser Doppler flowmetry combined with acetylcholine (Ach) and sodium nitroprusside (SNP) iontophoresis in 24 OSAS patients and 9 control patients. In 12 of the 24 OSAS patients, microvascular reactivity was reassessed after 2 months of CPAP and MAD using a randomized cross-over design.ResultsAch-induced vasodilation was significantly lower in OSAS patients than in matched controls and correlated negatively with apnea hypopnea index (r = ?0.49, p < 0.025) and nocturnal oxygen desaturations (r = ?0.63, p < 0.002). Ach-induced vasodilation increased significantly with both CPAP and MAD. The increase in Ach-induced vasodilation under OSAS treatment correlated with the decrease in nocturnal oxygen desaturations (r = 0.48, p = 0.016).ConclusionOur study shows an impairment of MVEF in OSAS related to OSAS severity. Both CPAP and MAD treatments were associated with an improvement in MVEF that could contribute to improve cardiovascular outcome in OSAS patients.     

A somatic NLRP3 mutation as a cause of a sporadic case of chronic infantile neurologic,cutaneous, articular syndrome/neonatal‐onset multisystem inflammatory disease: Novel evidence of the role of low‐level mosaicism as the pathophysiologic mechanism underlying mendelian inherited diseases

Objective

Chronic infantile neurologic, cutaneous, articular syndrome (CINCA), also known as neonatal‐onset multisystem inflammatory disease (NOMID), is a severe, early‐onset autoinflammatory disease characterized by an urticaria‐like rash, arthritis/arthropathy, variable neurologic involvement, and dysmorphic features, which usually respond to interleukin‐1 blockade. CINCA/NOMID has been associated with dominant Mendelian inherited NLRP3 mutations. However, conventional sequencing analyses detect true disease‐causing mutations in only ∼55–60% of patients, which suggests the presence of genetic heterogeneity. We undertook the current study to assess the presence of somatic, nongermline NLRP3 mutations in a sporadic case of CINCA/NOMID.

Methods

Clinical data, laboratory results, and information on treatment outcomes were gathered through direct interviews. Exhaustive genetic studies, including Sanger method sequencing, subcloning, restriction fragment length polymorphism assay, and pyrosequencing, were performed.

Results

The patient's CINCA/NOMID was diagnosed based on clinical features (early onset of the disease, urticaria‐like rash, knee arthropathy, and dysmorphic features). The patient has exhibited a successful response to anakinra within the last 28 months. Analysis of NLRP3 identified a novel heterozygous variant (p.D303H) that was detected in ∼30–38% of circulating leukocytes. The absence of this variant in healthy controls and in the patient's parents suggested a de novo true disease‐causing mutation. Additional analyses showed that this novel mutation was present in both leukocyte subpopulations and epithelial cells.

Conclusion

Our findings identify the novel p.D303H NLRP3 variant in a Spanish patient with CINCA/NOMID as a new disease‐causing mutation, which was detected as a somatic, nongermline mutation in hematopoietic and nonhematopoietic cell lineages. Our data provide new insight into the role of low‐level mosaicism in NLRP3 as the pathophysiologic mechanism underlying cryopyrin‐associated periodic syndrome.

     

Expanding the phenotypic spectrum of lupus erythematosus in Aicardi‐Goutières syndrome

Objective

Aicardi‐Goutières syndrome (AGS) is an early‐onset encephalopathy resembling congenital viral infection that is characterized by basal ganglia calcifications, loss of white matter, cerebrospinal fluid (CSF) lymphocytosis, and elevated interferon‐α levels in the CSF. Studies have shown that AGS is an autosomal‐recessive disease linked to mutations in 5 genes, encoding the 3′‐repair DNA exonuclease 1 (TREX1), the 3 subunits of ribonuclease H2 (RNASEH2A–C), and sterile alpha motif domain and HD domain–containing protein 1 (SAMHD1). In this study we further characterized the phenotypic spectrum of this disease.

Methods

Clinical and laboratory data were obtained from 26 patients fulfilling the clinical diagnostic criteria for AGS. Genomic DNA was screened for mutations in all 5 AGS genes by direct sequencing, and sera were analyzed for autoantibodies.

Results

In 20 patients with AGS, 20 mutations, 12 of which were novel, were identified in all 5 AGS genes. Clinical and laboratory investigations revealed a high prevalence of features (some not previously described in patients with AGS) that are commonly seen in patients with systemic lupus erythematosus (SLE), such as thrombocytopenia, leukocytopenia, antinuclear antibodies, erythematous lesions, oral ulcers, and arthritis, which were observed in 12 (60%) of 20 patients with AGS. Moreover, the coexistence of AGS and SLE, was for the first time, demonstrated in 2 patients with molecularly proven AGS.

Conclusion

These findings expand the phenotypic spectrum of lupus erythematosus in AGS and provide further insight into its disease mechanisms by showing that activation of the innate immune system as a result of inherited defects in nucleic acid metabolism could lead to systemic autoimmunity.

     

Encoding dysfunctions in a dynamic-static paradigm for visuospatial working memory in first-episode psychosis patients: a 2-year follow-up study

Aim: To investigate static and dynamic visuospatial working memory (VSWM) processes in first‐episode psychosis (FEP) patients and explore the validity of such measures as specific trait markers of schizophrenia. Methods: Twenty FEP patients and 20 age‐, sex‐, laterality‐ and education‐matched controls carried out a dynamic and static VSWM paradigm. At 2‐year follow up 13 patients met Diagnostic and Statistical Manual (of Mental Health Disorders) – Fourth Edition (DSM‐IV) criteria for schizophrenia, 1 for bipolar disorder, 1 for brief psychotic episode and 5 for schizotypal personality disorder. Results: Compared with controls, the 20 FEP patients showed severe impairment in the dynamic VSWM condition but much less impairment in the static condition. No specific bias in stimulus selection was detected in the two tasks. Two‐year follow‐up evaluations suggested poorer baseline scores on the dynamic task clearly differentiated the 13 FEP patients who developed schizophrenia from the seven who did not. Conclusions: Results suggest deficits in VSWM in FEP patients. Specific exploratory analyses further suggest that deficit in monitoring‐manipulation VSWM processes, especially involved in our dynamic VSWM task, can be a reliable marker of schizophrenia.     

Peritumoural vascular invasion: a major determinant of triple-negative breast cancer outcome

Purpose

Triple-negative breast cancers (TNBC) have the worst outcome of all breast cancer subtypes. Nevertheless TNBC are heterogeneous in terms of pathological, biological and prognostic behaviours. We explored clinical and pathological factors correlated with outcome in this phenotype.

Methods

We retrospectively studied clinical and pathological factors correlated with prognosis in a series of 344 early TNBC. Staining for blood (CD31) and lymphatic (Podoplanin) vascular endothelium markers was performed to best characterise peritumoural vascular invasion (PVI) in 108 cases available for pathological reviewing.

Results

Univariate and multivariate analyses performed on our whole cohort underlined PVI as an independent predictive factor of distant metastasis (p = 0.00012, HR = 2.72 [1.63-4.52]). Standardised pathological reviewing of 101 histologically confirmed TNBC showed that PVI, observed in 41% (28% by haematoxylin and eosin staining plus 13% by immunohistochemistry), was confirmed as the first prognostic factor in TNBC, particularly in node-negative tumours. Five-year metastasis-free survival in this subset was 87.5% and 50.8% without and with PVI, respectively (p = 0.003).

Conclusions

Vascular invasion diagnosis is improved by the combination of HES and IHC. Moreover it is a major prognostic feature and must take a greater part in therapeutic management of early TNBC with the possibility to adapt the adjuvant treatment according to the predicted relapse risk.     

Espace de parole en prévention du syndrome de <Emphasis Type="Italic">burnout</Emphasis> : deux ans d’expérience au sein de l’Association des jeunes oncologues bas-normands (Ajon)

The plight of doctors, especially the residents, still receives little attention although the burnout syndrome is a reality. The Association of Young Oncologists from Low Normandy has developed think tanks about the patient-physician relationship to create a space for exchange. The meetings are led by an oncologist or a psychologist. This device provides support and helps to step back from difficult situations. It is an aid and training to better manage the stress inherent in our clinical practice with patients and/or their relatives.