Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma

Peripheral T-cell lymphoma (PTCL) encompasses a heterogeneous group of neoplasms with generally poor clinical outcome. Currently 50% of PTCL cases are not classifiable: PTCL-not otherwise specified (NOS). Gene-expression profiles on 372 PTCL cases were analyzed and robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for major PTCL-entities, including 114 angioimmunoblastic T-cell lymphoma (AITL), 31 anaplastic lymphoma kinase (ALK)-positive and 48 ALK-negative anaplastic large cell lymphoma, 14 adult T-cell leukemia/lymphoma and 44 extranodal NK/T-cell lymphoma that were further separated into NK-cell and gdT-cell lymphomas. Thirty-seven percent of morphologically diagnosed PTCL-NOS cases were reclassified into other specific subtypes by molecular signatures. Reexamination, immunohistochemistry, and IDH2 mutation analysis in reclassified cases supported the validity of the reclassification. Two major molecular subgroups can be identified in the remaining PTCL-NOS cases characterized by high expression of either GATA3 (33%; 40/121) or TBX21 (49%; 59/121). The GATA3 subgroup was significantly associated with poor overall survival (P = .01). High expression of cytotoxic gene-signature within the TBX21 subgroup also showed poor clinical outcome (P = .05). In AITL, high expression of several signatures associated with the tumor microenvironment was significantly associated with outcome. A combined prognostic score was predictive of survival in an independent cohort (P = .004).

Peripheral neuropathy is linked to a severe form of myotonic dystrophy in transgenic mice.

Myotonic dystrophy type 1 (DM1) is a multisystem disorder with a variable phenotype. The involvement of peripheral nerves in DM1 disease is controversial. The DM1 animal model DM300 transgenic mice that carry 350 to 500 CTG repeats express a mild DM1 phenotype but do not exhibit motor or sensory pathology. Here, we investigated the presence or absence of peripheral neuropathy in transgenic mice (DMSXL) that carry more than 1,300 CTG repeats and display a severe form of DM1. Electrophysiologic, histologic, and morphometric methods were used to investigate the structure and function of peripheral nerves. We observed lower compound muscle action potentials recorded from hind limb muscles and slowing of sciatic nerve conduction velocity in DMSXL versus control mice. Morphometric analyses showed an axonopathy and neuronopathy in the DMSXL mice characterized by a decrease in numbers of myelinatedmotor axons in sciatic nerve and in spinal cord motor neurons. Pathologic alterations in the structure of hind limb neuromuscular junctions were also detected in the DMSXL mice. These results suggest that peripheral neuropathy can be linked to a large CTG expansion and a severe form of DM1.

L'hépatectomie réglée. A propos de 18 cas opérés dans un hôpital périphérique [Standardized hepatectomy. 18 cases operated in a peripheral hospital]

Hepatectomy has long been a formidable surgical procedure because the risk of hemorrhage it can involve. With a better understanding of hepatic anatomy, left hepatectomy, right hepatectomy and segmental hepatic resections have been standardized. Between January 1989 and December 1992, 18 hepatectomies were performed on 16 patients in the Department of Surgery, General Hospital, La Chaux-de-Fonds, Switzerland. The mean age of the patients was 65. The surgical indications were: hepatic metastases 11 (61%); gallbladder or biliary duct neoplasm 4 (22%); hydatic cyst 3 (17%). 11 segmental resection, 3 left hepatectomies, 2 right hepatectomies, 2 pericystectomies were performed. Blood loss during these operations averaged 2800 ml. Surgical complications appeared in 6 cases (hemorrhage 1, postoperative effusion 4, sepsis 1). One patient died within 30 days (mortality 5%). Hepatectomy is nowadays a safe procedure. It can be performed in a general hospital with a trained surgical team and an efficient intensive care unit

Group 4: Career development for diverse and underserved populations

Globalization and diverse populations due to migration imply that counselors are expected to deliver career services to populations from a large array of cultural settings. Moreover, individuals belonging to minority or non-dominant groups may be underserved or misserved, thus decreasing their chances of finding employment opportunities through career counseling. To develop specific interventions minority or non-dominant groups, it seems important to understand their strength and weaknesses. These strengths and weaknesses will be presented in terms of risk and resilience factors, such as low future orientation and social support respectively. In the last two decades, several authors have made contributions to adapt and improve career services in order to best meet these minority groups' needs. A review of this literature identified thirteen keys to effective practice. For example, one key is to take responsibility for one's own biases and prejudices. Nonetheless, some underserved groups remain difficult to identify. Comparing some basic national demographic data with data from our counseling centers may be helpful in this context in identifying specific groups and assessing needs. One solution, in order to promote social justice across (all) cultural groups, is to encourage multiculturalism in both career counseling and society as a whole. A more inclusive society would allow each person in a minority or non-dominant group to contribute more effectively to the development and growth of this society.

Pairing of Vbeta6 with certain Valpha2 family members prevents T cell deletion by Mtv-7 superantigen.

Superantigens (SAg) are proteins of bacterial or viral origin able to activate T cells by forming a trimolecular complex with both MHC class II molecules and the T cell receptor (TCR), leading to clonal deletion of reactive T cells in the thymus. SAg interact with the TCR through the beta chain variable region (Vbeta), but the TCR alpha chain has been shown to have an influence on the T cell reactivity. We have investigated here the role of the TCR alpha chain in the modulation of T cell reactivity to Mtv-7 SAg by comparing the peripheral usage of Valpha2 in Vbeta6(+) (SAg-reactive) and Vbeta8.2(+) (SAg non-reactive) T cells, in either BALB/D2 (Mtv-7(+)) or BALB/c (Mtv-7(-)) mice. The results show, first, that pairing of Vbeta6 with certain Valpha2 family members prevents T cell deletion by Mtv-7 SAg. Second, there is a strikingly different distribution of the Valpha2 family members in CD4 and CD8 populations of Vbeta6 but not of Vbeta8.2 T cells, irrespective of the presence of Mtv-7 SAg. Third, the alpha chain may play a role in the overall stability of the TCR/SAg/MHC complex. Taken together, these results suggest that the Valpha domain contributes to the selective process by its role in the TCR reactivity to SAg/MHC class II complexes, most likely by influencing the orientation of the Vbeta domain in the TCR alphabeta heterodimer.

Comparing connectomes across subjects and populations at different scales.

Brain connectivity can be represented by a network that enables the comparison of the different patterns of structural and functional connectivity among individuals. In the literature, two levels of statistical analysis have been considered in comparing brain connectivity across groups and subjects: 1) the global comparison where a single measure that summarizes the information of each brain is used in a statistical test; 2) the local analysis where a single test is performed either for each node/connection which implies a multiplicity correction, or for each group of nodes/connections where each subset is summarized by one single test in order to reduce the number of tests to avoid a penalizing multiplicity correction. We comment on the different levels of analysis and present some methods that have been proposed at each scale. We highlight as well the possible factors that could influence the statistical results and the questions that have to be addressed in such an analysis.

Peripheral dual-energy X-ray absorptiometry in the management of osteoporosis: the 2007 ISCD Official Positions.

Peripheral assessment of bone density using photon absorptiometry techniques has been available for over 40 yr. The initial use of radio-isotopes as the photon source has been replaced by the use of X-ray technology. A wide variety of models of single- or dual-energy X-ray measurement tools have been made available for purchase, although not all are still commercially available. The Official Positions of the International Society for Clinical Densitometry (ISCD) have been developed following a systematic review of the literature by an ISCD task force and a subsequent Position Development Conference. These cover the technological diversity among peripheral dual-energy X-ray absorptiometry (pDXA) devices; define whether pDXA can be used for fracture risk assessment and/or to diagnose osteoporosis; examine whether pDXA can be used to initiate treatment and/or monitor treatment; provide recommendations for pDXA reporting; and review quality assurance and quality control necessary for effective use of pDXA.

A clinical pattern-based etiological diagnostic strategy for sensory neuronopathies: a French collaborative study.

Sensory neuronopathies (SNNs) encompass paraneoplastic, infectious, dysimmune, toxic, inherited, and idiopathic disorders. Recently described diagnostic criteria allow SNN to be differentiated from other forms of sensory neuropathy, but there is no validated strategy based on routine clinical investigations for the etiological diagnosis of SNN. In a multicenter study, the clinical, biological, and electrophysiological characteristics of 148 patients with SNN were analyzed. Multiple correspondence analysis and logistic regression were used to identify patterns differentiating between forms of SNNs with different etiologies. Models were constructed using a study population of 88 patients and checked using a test population of 60 cases. Four patterns were identified. Pattern A, with an acute or subacute onset in the four limbs or arms, early pain, and frequently affecting males over 60 years of age, identified mainly paraneoplastic, toxic, and infectious SNN. Pattern B identified patients with progressive SNN and was divided into patterns C and D, the former corresponding to patients with inherited or slowly progressive idiopathic SNN with severe ataxia and electrophysiological abnormalities and the latter to patients with idiopathic, dysimmune, and sometimes paraneoplastic SNN with a more rapid course than in pattern C. The diagnostic strategy based on these patterns correctly identified 84/88 and 58/60 patients in the study and test populations, respectively.

Adaptive diversity in heterogeneous environments for populations regulated by a mixture of soft and hard selection

The stable co-existence of two haploid genotypes or two species is studied in a spatially heterogeneous environment submitted to a mixture of soft selection (within-patch regulation) and hard selection (outside-patch regulation) and where two kinds of resource are available. This is analysed both at an ecological time-scale (short term) and at an evolutionary time-scale (long term). At an ecological scale, we show that co-existence is very unlikely if the two competitors are symmetrical specialists exploiting different resources. In this case, the most favourable conditions are met when the two resources are equally available, a situation that should favour generalists at an evolutionary scale. Alternatively, low within-patch density dependence (soft selection) enhances the co-existence between two slightly different specialists of the most available resource. This results from the opposing forces that are acting in hard and soft regulation modes. In the case of unbalanced accessibility to the two resources, hard selection favours the most specialized genotype, whereas soft selection strongly favours the less specialized one. Our results suggest that competition for different resources may be difficult to demonstrate in the wild even when it is a key factor in the maintenance of adaptive diversity. At an evolutionary scale, a monomorphic invasive evolutionarily stable strategy (ESS) always exists. When a linear trade-off exists between survival in one habitat versus that in another, this ESS lies between an absolute adjustment of survival to niche size (for mainly soft-regulated populations) and absolute survival (specialization) in a single niche (for mainly hard-regulated populations). This suggests that environments in agreement with the assumptions of such models should lead to an absence of adaptive variation in the long term.

ROLES OF ACID-SENSING ION CHANNELS (ASICS) IN PERIPHERAL NEUROPEPTIDE SECRETION AND PAIN

Acid-sensing ion channels (ASICs) are non-voltage-gated sodium channels activated by an extracellular acidification. They are widely expressed in neurons of the central and peripheral nervous system. ASICs have a role in learning, the expression of fear, in neuronal death after cerebral ischemia, and in pain sensation. Tissue damage leads to the release of inflammatory mediators. There is a subpopulation of sensory neurons which are able to release the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). Neurogenic inflammation refers to the process whereby peripheral release of the neuropeptides CGRP and SP induces vasodilation and extravasation of plasma proteins, respectively. Our laboratory has previously shown that calcium-permeable homomeric ASIC1a channels are present in a majority of CGRP- or SP-expressing small diameter sensory neurons. In the first part of my thesis, we tested the hypothesis that a local acidification can produce an ASIC-mediated calcium-dependant neuropeptide secretion. We have first verified the co-expression of ASICs and CGRP/SP using immunochemistry and in-situ hybridization on dissociated rat dorsal root ganglion (DRG) neurons. We found that most CGRP/SP-positive neurons also expressed ASIC1a and ASIC3 subunits. Calcium imaging experiments with Fura-2 dye showed that an extracellular acidification can induce an increase of intracellular Ca2+ concentration, which is essential for secretion. This increase of intracellular Ca2+ concentration is, at least in some cells, ASIC-dependent, as it can be prevented by amiloride, an ASIC antagonist, and by Psalmotoxin (PcTx1), a specific ASIC1a antagonist. We identified a sub-population of neurons whose acid-induced Ca2+ entry was completely abolished by amiloride, an amiloride-resistant population which does not express ASICs, but rather another acid-sensing channel, possibly transient receptor potential vanilloïde 1 (TRPV1), and a population expressing both H+-gated channel types. Voltage-gated calcium channels (Cavs) may also mediate Ca2+ entry. Co-application of the Cavs inhibitors (ω-conotoxin MVIIC, Mibefradil and Nifedipine) reduced the Ca2+ increase in neurons expressing ASICs during an acidification to pH 6. This indicates that ASICs can depolarise the neuron and activate Cavs. Homomeric ASIC1a are Ca2+-permeable and allow a direct entry of Ca2+ into the cell; other ASICs mediate an indirect entry of Ca2+ by inducing a membrane depolarisation that activates Cavs. We showed with a secretion assay that CGRP secretion can be induced by extracellular acidification in cultured rat DRG neurons. Amiloride and PcTx1 were not able to inhibit the secretion at acidic pH, but BCTC, a TRPV1 inhibitor was able to decrease the secretion induced by an extracellular acidification in our in vitro secretion assay. In conclusion, these results show that in DRG neurons a mild extracellular acidification can induce a calcium-dependent neuropeptide secretion. Even if our data show that ASICs can mediate an increase of intracellular Ca2+ concentration, this appears not to be sufficient to trigger neuropeptide secretion. TRPV1, a calcium channel whose activation induces a sustained current - in contrary of ASICs - played in our experimental conditions a predominant role in neurosecretion. In the second part of my thesis, we focused on the role of ASICs in neuropathic pain. We used the spared nerve injury (SNI) model which consists in a nerve injury that induces symptoms of neuropathic pain such as mechanical allodynia. We have previously shown that the SNI model modifies ASIC currents in dissociated rat DRG neurons. We hypothesized that ASICs could play a role in the development of mechanical allodynia. The SNI model was performed on ASIC1a, -2, and -3 knock-out mice and wild type littermates. We measured mechanical allodynia on these mice with calibrated von Frey filaments. There were no differences between the wild-type and the ASIC1, or ASIC2 knockout mice. ASIC3 null mice were less sensitive than wild type mice at 21 day after SNI, indicating a role for ASIC3. Finally, to investigate other possible roles of ASICs in the perception of the environment, we measured the baseline heat responses. We used two different models; the tail flick model and the hot plate model. ASIC1a null mice showed increased thermal allodynia behaviour in the hot plate test at three different temperatures (49, 52, 55°C) compared to their wild type littermates. On the contrary, ASIC2 null mice showed reduced thermal allodynia behaviour in the hot plate test compared to their wild type littermates at the three same temperatures. We conclude that ASIC1a and ASIC2 in mice can play a role in temperature sensing. It is currently not understood how ASICs are involved in temperature sensing and what the reason for the opposed effects in the two knockout models is.