Precision medicine for KRAS wild-type pancreatic adenocarcinomas.

BACKGROUND: KRAS mutation is the most common molecular alteration in pancreatic adenocarcinoma (PDAC), and around 10% of patients harbor KRAS wild-type tumors (KRASWT). METHODS: A retrospective chart review of clinical/molecular data was performed including all PDAC patients with a determined KRAS status (tumor molecular profiling on tissue or liquid biopsy). RESULTS: 342 patients were included with 54 KRASWT PDAC (16%) compared to 288 patients with KRASm PDAC. Median age was 61 years [IQR:54.0;67.0] and 164 pts (48%) were female. At diagnosis, KRASWT patients (63%) were more frequently diagnosed at a non-metastatic stage compared to KRASm patients (41%) (p = 0.003). Regarding metastatic sites, liver was less frequent in KRASWT (39%, p < 0.0001). Median overall survival (mOS) from initial diagnosis was significantly higher in the KRASWT group compared to KRASm (50.8 months, CI95% [32.0-NR] vs 21.1 months, CI95% [18.9-23.4] (p < 0.004 after adjustment on age, ECOG and stage at diagnosis). In first-line systemic treatment, (mostly FOLFIRINOX) progression-free survival (PFS) was also higher in KRASWT. Based on ESCAT classification, a putative actionable alteration (ESCAT I-III) was identified in 19 (36%) KRASWT pts and 46 (16%) KRASm patients (p < 0.0001) with more alterations in FGFR2, BRAF(V600E), NRTK and more MSI tumors. KRASWT harbored also fewer alterations in TP53, CDKN2A, and SMAD4. 12 KRASWT patients received a molecularly-matched treatment with clinical benefit and improved outcomes compared to KRASm patients. CONCLUSIONS: KRASWT patients display distinct disease characteristics and outcomes with prolonged overall survival. KRASWT patients also harbor more actionable molecular alterations, leading to higher survival rates after receiving molecularly matched treatments.

Integrated biomarker response to assess the effects of pesticide residues on Nile Tilapia in aquatic ecosystems contaminated by cotton-field effluents.

An in-situ study combined with an integrated biomarker response was used to evaluate the impact of agricultural effluents in the physiological responses of Nile tilapia reared in cages and enclosures of water reservoirs in North Benin. Fish were distributed in fish farming systems at two sites: Songhai located outside the cotton basin and Batran located in the most productive commune. They were sampled for blood and organs before (BST), during (DST) and after (AST) pesticide treatment. Pesticide residues were analysed in water, sediments and fish muscles. Several biomarkers were investigated related to the immune (peroxidase, lysozyme and complement activities, superoxide anion production) and reproductive (sex steroids and vitellogenin levels) responses as well as neurotoxicity (cholinesterase activity) and tissue alterations. Biomarkers were assessed and analysed via the integrated biomarker response (IBR). The results showed that Batran water reservoir was a more harmful ecosystem for fish than Songhai one, especially by depressing some immune and reproductive functions in relation to a higher-level of pesticide contamination. They also demonstrated that the contact of fish to sediments in enclosures aggravated the pesticide burden on fish. Therefore, using males as bioindicators would improve the sensitivity of the used biomarkers since males seemed more affected than females especially due to pesticide estrogenic induction impacting their reproductive system.

Chronic effects of a binary insecticide Acer 35 EC on Nile tilapia Oreochromis niloticus through a multi-biomarker approach.

Acer 35 EC is a widely used insecticide (a binary mixture of lambda-cyhalothrin and acetamiprid) in pest control in many West African countries, particularly in the cotton culture in north Benin. The aim of this study was to investigate the chronic effects of Acer 35 EC on Nile tilapia Oreochromis niloticus juveniles using a multi-biomarker approach under laboratory conditions. For this purpose, fish were exposed to sublethal concentrations of Acer 35 EC (0, 1 and 10% of LC50- 96 h value). After 28 and 56 days of exposure, several biomarkers were measured in males and females including enzymatic activities related to detoxification and oxidative stress, neurotoxicity and immune responses, sex steroid hormones (testosterone, 17ß-estradiol and 11-keto-testosterone) and histological alterations of liver, kidney and gonads. An Integrated Biomarker Response (IBR) was then calculated. The results showed a reduction of cholinesterase activity in muscles, and intercellular superoxide anion production in both sexes. Female steroidogenesis and gametogenesis were affected, especially testosterone levels and oocyte growth. More alterations were observed in liver after exposure to Acer 35 EC. In both sexes, IBR values were higher after 56 days than after 28 days of exposure. In conclusion, based on a large set of biomarkers and IBR values, the chronic exposure to low doses of insecticide Acer 35 EC seems to impair different physiological functions in Nile tilapia juveniles on a time-dependent manner, with a stronger impact on females than on males.

Impact of downstream passage through hydropower plants on the physiological and health status of a critically endangered species: The European eel Anguilla anguilla.

Hydropower plants (HPPs) are a source of "green" energy but also a threat to migrating fish such as the European eel (Anguilla anguilla) owing to the disruption of river connectivity and the obstruction of downstream migration. The impact of HPP are well-documented in terms of fish survival and damages but there is no available information concerning the condition of surviving and unharmed fish. The aim of this study is to assess the impact of the passage through HPP on the survival, the physiological and health status of adult eels. Two trials were carried with variants of the Kaplan turbine - one of the most common types in Europe. After a deliberate passage through the turbines, we studied direct mortality, external and internal damages, stress and immune biomarkers such as plasma cortisol and glucose levels, alternative complement (ACH50), lysozyme and peroxidase activities, and total immunoglobulin (Ig) content. Our results showed a lower survival and a higher external and internal damages rates in the HPP groups. Glucose levels, ACH50, lysozyme and peroxidase activities and TIgc were also affected by the passage depending on HPP characteristics. Those findings suggest a greater energy expenditure and a disruption in innate immunity due to this passage. HPPs can not only have an impact in terms of direct mortality and injuries but also affect the physiological and health condition of the surviving eels. This impact may explain the delayed mortality observed in telemetric studies and the passage through many HPPs may compromise the ability of adult eels to migrate successfully to the ocean.

First identification of dopamine receptors in pikeperch, Sander lucioperca, during the pre-ovulatory period.

Dopamine (DA) is a ubiquitous neurotransmitter exerting a range of pleiotropic actions through two DA receptor families, the D1 and the D2. To date in vertebrates, a maximum of four receptor subtypes have been identified within the D1 family, D1 (former D1A), D5 (former D1B), D6 (former D1C and D1D) and D7 (former D1E), while the D2 family encloses five subtypes, D2, D3, D4, D8 (former D2like or D2l) and D9 (former D4-related sequence or D4-rs). In teleosts, no study has investigated in parallel all the DA receptors to identify and localize the whole receptor repertoire from both families. In pikeperch, Sander lucioperca, a species of interest for aquaculture development, the existence, number and location of the DA receptors are totally unknown. To address these questions, RNA-seq with de novo transcriptome reconstruction, functional annotation and phylogenetic analysis were performed to characterize the transcript repertoire of DA receptors in the brain of female pikeperch at the pre-ovulatory period. Ten different cDNA were identified and showed to belong to the D1 family: two D1, one D5a, one D6a and one D6b and to the D2 family: two spliced variants of D2, one D3, one D8 and one D9. Unlike zebrafish, the subtypes D4 and D7 have not yet been isolated in pikeperch. As expected D1, D3, D8 and D9 are mostly expressed in brain parts except for the cerebellum (D1 and D3). The inter-species differences in the number of DA receptors and the inter-organ differences in the gene expression of all receptors support the complexity of the dopaminergic actions in vertebrate.

Passage through a hydropower plant affects the physiological and health status of Atlanstic salmon smolts.

Atlantic salmon is an anadromous species migrating from upper-reach nursery areas in rivers to the oceanic feeding areas at smolt stage and inversely at adult stage requiring unimpeded migration routes. However, dams associated with hydroelectric power plants (HPP) disrupt river connectivity and affect fish movement and survival. The objective of the current study was to evaluate the short and mid-term physiological and immune response of Atlantic salmon smolts after passing through Andenne HPP (Meuse River, Belgium). Several parameters were studied after an in situ deliberate passage including direct mortality and external damages, stress and immune biomarkers as plasma cortisol and glucose levels, complement and peroxidase activities, and immune and oxidative stress related gene expression 24 h, 72 h and 120 h after passage. Survival rate was lower and external damages were more important in fish that confronted the HPP compared to the control ones. Moreover, the passage through the turbine affected plasma glucose levels, complement and peroxidase activities and the expression of some immune genes such as lysg, igm and mpo in a timely manner suggesting that this passage can lead to a great energy expenditure and a disruption of innate immunity. Our observations can partially explain the delayed mortality observed in many studies leading to a poor success of restocking programs. HPPs not only have a direct impact in terms of mortalities and injuries but also an indirect one in terms of physiological and immune changes that can compromise Atlantic salmon smolts ability to escape successfully to the ocean.

Repeated hormonal induction of spermiation affects the stress but not the immune response in pikeperch (Sander lucioperca).

Hormonal induction of spermiation, previously reported to be immunogenic in fishes, is a common hatchery practice in pikeperch, Sander lucioperca. The aim of the present study was to investigate the effects of repeated induction of spermiation in pikeperch, following application of either human chorionic gonadotropin (hCG) or salmon gonadoliberine analogue (sGnRHa) on sperm quality indices as well as on immune and stress response. Mature males of pikeperch (n = 7 per group) were stimulated twice with five days between injections of either hCG (hCG; 500 IU kg-1), sGnRHa (sGnRHa; 50 µg kg-1) or NaCl (control group; 1 ml kg-1) to assess spermatozoa motility with a computer-assisted sperm analysis (CASA) system. During second sampling, blood plasma was sampled for humoral innate immune (peroxidase and lysozyme activities, ACH50), stress (cortisol, glucose) and endocrine (testosterone) markers. In addition, the head kidney was dissected to assay the expression of several immune genes (such as il1, c3, hamp, tnf-α and lys genes). The results indicate that hormonal treatment significantly increased sperm production. Sperm sampled after the hormonal treatment maintained its quality throughout the study, regardless of the sampling time. However, it appears that the application of hCG induced elevated cortisol and glucose plasma levels compared to the control group. Almost all immune markers, except the relative expression of hepcidin (hamp gene), were unaffected by the two hormones applied. The results showed that the induction treatment of spermiation processes in pikeperch resulted in an important physiological stress response for which the intensity varied according to the hormonal agent used. However, this stress response (more profound following application of hCG) was weakly associated with innate immune functions. On the other hand, a significant negative correlation between the expression of several important immune markers (peroxidase activity, relative expression of c3 and il1 genes) and sperm quality indices indicates significant involvement of immune status on sperm quality. The results obtained shed light on immune-system-induced modifications to sperm quality. The data presented here highlight the need for careful revision of broodstock management and selection practices where welfare status as well as individual predispositions of fish to cope with the stress should be taken under the consideration.

Constant long photoperiod inhibits the onset of the reproductive cycle in roach females and males.

Photoperiod and temperature are commonly accepted as the determinant factors for the control of the reproductive cycle in freshwater fishes. However, this determining effect is dependent on fish species. While applying a constant long photoperiod has an inhibitory effect in some species, the same photoperiodic manipulation has a stimulating effect in others. In cyprinids, a decrease in temperature or photoperiod can induce the gonad recrudescence. However, in roach Rutilus rutilus an early spring spawner cyprinid, there is little knowledge about the cueing role of each environmental factor. The aim of this work was to study the effect of a constant long photoperiod on the gametogenesis in roach. Fish were kept under either naturally simulated photoperiod or artificial constant long photoperiod and sampled at three times: at the beginning of photoperiod decrease, at the beginning of temperature decrease, and at the end of temperature decrease. Morphological parameters (gonado-somatic, hepato-somatic, and viscera-somatic indexes), plasma sexual steroids, and proportion of gametogenesis stages were estimated at each sampling time. The results showed that a constant, long photoperiod exerted inhibitory effects on gametogenesis advancement in both females and males that could stem from decrease of sex steroid production. Roach displayed a similar response to photoperiodic manipulations to other early spring spawners like percids, such as European perch, yellow perch and pikeperch. These results clearly showed the cueing role of the photoperiod in the induction of the reproductive cycle in roach.

Appraisal of unimodal cues during agonistic interactions in Maylandia zebra.

Communication is essential during social interactions including animal conflicts and it is often a complex process involving multiple sensory channels or modalities. To better understand how different modalities interact during communication, it is fundamental to study the behavioural responses to both the composite multimodal signal and each unimodal component with adequate experimental protocols. Here we test how an African cichlid, which communicates with multiple senses, responds to different sensory stimuli in a social relevant scenario. We tested Maylandia zebra males with isolated chemical (urine or holding water coming both from dominant males), visual (real opponent or video playback) and acoustic (agonistic sounds) cues during agonistic interactions. We showed that (1) these fish relied mostly on the visual modality, showing increased aggressiveness in response to the sight of a real contestant but no responses to urine or agonistic sounds presented separately, (2) video playback in our study did not appear appropriate to test the visual modality and needs more technical prospecting, (3) holding water provoked territorial behaviours and seems to be promising for the investigation into the role of the chemical channel in this species. Our findings suggest that unimodal signals are non-redundant but how different sensory modalities interplay during communication remains largely unknown in fish.

Synaptic Regulation of a Thalamocortical Circuit Controls Depression-Related Behavior.

The NMDA receptor (NMDAR) antagonist ketamine elicits a long-lasting antidepressant response in patients with treatment-resistant depression. Understanding how antagonism of NMDARs alters synapse and circuit function is pivotal to developing circuit-based therapies for depression. Using virally induced gene deletion, ex vivo optogenetic-assisted circuit analysis, and in vivo chemogenetics and fMRI, we assessed the role of NMDARs in the medial prefrontal cortex (mPFC) in controlling depression-related behavior in mice. We demonstrate that post-developmental genetic deletion of the NMDAR subunit GluN2B from pyramidal neurons in the mPFC enhances connectivity between the mPFC and limbic thalamus, but not the ventral hippocampus, and reduces depression-like behavior. Using intersectional chemogenetics, we show that activation of this thalamocortical circuit is sufficient to elicit a decrease in despair-like behavior. Our findings reveal that GluN2B exerts input-specific control of pyramidal neuron innervation and identify a medial dorsal thalamus (MDT)→mPFC circuit that controls depression-like behavior.