Effects of Side Chain and Peptide Bond Modifications on the Targeting Properties of Stabilized Minigastrin Analogs.

Different attempts have been made in the past two decades to develop radiolabeled peptide conjugates with enhanced pharmacokinetic properties in order to improve the application for tumor imaging and peptide receptor radionuclide therapy (PRRT), which targets the cholecystokinin-2 receptor (CCK2R). In this paper, the influence of different side chain and peptide bond modifications has been explored for the minigastrin analog DOTA-DGlu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1Nal-NH2 (DOTA-MGS5). Based on this lead structure, five new derivatives were synthesized for radiolabeling with trivalent radiometals. Different chemical and biological properties of the new derivatives were analyzed. Receptor interaction of the peptide derivatives and cell internalization of the radiolabeled peptides were studied in A431-CCK2R cells. The stability of the radiolabeled peptides in vivo was investigated using BALB/c mice. Tumor targeting of all 111In-labeled peptide conjugates, and of a selected compound radiolabeled with gallium-68 and lutetium-177, was evaluated in BALB/c nude mice xenografted with A431-CCK2R and A431-mock cells. All 111In-labeled conjugates, except [111In]In-DOTA-[Phe8]MGS5, showed a high resistance against enzymatic degradation. A high receptor affinity with IC50 values in the low nanomolar range was confirmed for most of the peptide derivatives. The specific cell internalization over time was 35.3-47.3% for all radiopeptides 4 h after incubation. Only [111In]In-DOTA-MGS5[NHCH3] exhibited a lower cell internalization of 6.6 ± 2.8%. An overall improved resistance against enzymatic degradation was confirmed in vivo. Of the radiopeptides studied, [111In]In-DOTA-[(N-Me)1Nal8]MGS5 showed the most promising targeting properties, with significantly increased accumulation of radioactivity in A431-CCK2R xenografts (48.1 ± 9.2% IA/g) and reduced accumulation of radioactivity in stomach (4.2 ± 0.5% IA/g). However, in comparison with DOTA-MGS5, a higher influence on the targeting properties was observed for the change of radiometal, resulting in a tumor uptake of 15.67 ± 2.21% IA/g for [68Ga]Ga-DOTA-[(N-Me)1Nal8]MGS5 and 35.13 ± 6.32% IA/g for [177Lu]Lu-DOTA-[(N-Me)1Nal8]MGS5.

Challenges in glioblastoma research: focus on the tumor microenvironment.

Glioblastoma (GBM) is the most deadly type of malignant brain tumor, despite extensive molecular analyses of GBM cells. In recent years, the tumor microenvironment (TME) has been recognized as an important player and therapeutic target in GBM. However, there is a need for a full and integrated understanding of the different cellular and molecular components involved in the GBM TME and their interactions for the development of more efficient therapies. In this review, we provide a comprehensive report of the GBM TME, which assembles the contributions of physicians and translational researchers working on brain tumor pathology and therapy in France. We propose a holistic view of the subject by delineating the specific features of the GBM TME at the cellular, molecular, and therapeutic levels.

Cognitive assessment in patients treated by immunotherapy: the prospective Cog-Immuno trial.

BACKGROUND: The discovery of the importance of the immune system and its role in oncogenesis led to the development of immunotherapy, a treatment that represents a major advance in oncology management. Due to the recent nature of immunotherapy, little is known about its side effects and their impact on quality of life. To date, there is no published study that accurately assesses the impact of immunotherapy on cognition, mood and/or fatigue in patients treated for cancer, despite potential neurological toxicities. The purpose of this study is to prospectively assess the incidence of cognitive impairment and cognitive complaints among cancer patients naïve for immunotherapy without concomitant anti-cancer treatment. METHODS: The Cog-Immuno trial is a multicentre longitudinal study addressing patients with cancer candidate to receive immunotherapy alone (n = 100). Immunotherapy treatment will include either anti-PD1/PDL1 or anti-CTLA4 monotherapy or combination therapy. Cognitive and quality of life assessment, electrocardiogram (ECG) and biological tests will be performed at baseline, thereafter 3, and 6 months after immunotherapy initiation. The primary endpoint is the proportion of patients treated by immunotherapy who will experience a decline in cognitive performances or in Montreal Cognitive Assessment (MoCA) score within 3 months after inclusion. Secondary endpoints concern: anxiety, depression, fatigue, clinical characteristics, biological data and neurophysiological measures (heart rate variability and hemispheric lateralization). A pre-clinical study will be conducted in cancer bearing mice receiving checkpoint inhibitors (ICI) with the evaluation of cognitive functions and emotional reactivity, collection of blood samples and investigation of neurobiological mechanisms from brain slices. DISCUSSION: Assessing and understanding the incidence and the severity of cognitive impairment and its impact on quality of life in cancer patients treated by immunotherapy is a major issue. The results of this study will provide information on the impact of these treatments on cognitive functions in order to help the physicians in the choice of the treatment. TRIAL REGISTRATION: NCT03599830, registered July 26, 2018. PROTOCOL VERSION: Version 5.1 dated from 2020/10/02.

Cancer-related cognitive impairment in non-CNS cancer patients: Targeted review and future action plans in Europe.

Cancer-related cognitive impairment (CRCI) has increasingly been identified over the last two decades in non-CNS system cancer patients. Across Europe, researchers have contributed to this effort by developing preclinical models, exploring underlying mechanisms and assessing cognitive and quality of life changes. The ultimate goal is to develop interventions to treat patients experiencing CRCI. To do so, new challenges need to be addressed requiring the implementation of multidisciplinary research groups. In this consensus paper, we summarize the state of the art in the field of CRCI combined with the future challenges and action plans in Europe. These challenges include data sharing/pooling, standardization of assessments as well as assessing additional biomarkers and neuroimaging investigations, notably through translational studies. We conclude this position paper with specific actions for Europe based on shared scientific expert opinion and stakeholders involved in the Innovative Partnership for Action Against Cancer, with a particular focus on cognitive intervention programs.

A Panax quinquefolius-Based Preparation Prevents the Impact of 5-FU on Activity/Exploration Behaviors and Not on Cognitive Functions Mitigating Gut Microbiota and Inflammation in Mice.

Chemotherapy-related cognitive impairment (CRCI) and fatigue constitute common complaints among cancer patient survivors. Panax quinquefolius has been shown to be effective against fatigue in treated cancer patients. We developed a behavioral C57Bl/6j mouse model to study the role of a Panax quinquefolius-based solution containing vitamin C (Qiseng®) or vitamin C alone in activity/fatigue, emotional reactivity and cognitive functions impacted by 5-Fluorouracil (5-FU) chemotherapy. 5-FU significantly reduces the locomotor/exploration activity potentially associated with fatigue, evokes spatial cognitive impairments and leads to a decreased neurogenesis within the hippocampus (Hp). Qiseng® fully prevents the impact of chemotherapy on activity/fatigue and on neurogenesis, specifically in the ventral Hp. We observed that the chemotherapy treatment induces intestinal damage and inflammation associated with increased levels of Lactobacilli in mouse gut microbiota and increased expression of plasma pro-inflammatory cytokines, notably IL-6 and MCP-1. We demonstrated that Qiseng® prevents the 5-FU-induced increase in Lactobacilli levels and further compensates the 5-FU-induced cytokine release. Concomitantly, in the brains of 5-FU-treated mice, Qiseng® partially attenuates the IL-6 receptor gp130 expression associated with a decreased proliferation of neural stem cells in the Hp. In conclusion, Qiseng® prevents the symptoms of fatigue, reduced chemotherapy-induced neuroinflammation and altered neurogenesis, while regulating the mouse gut microbiota composition, thus protecting against intestinal and systemic inflammation.

Chemotactic cell migration: the core autophagy protein ATG9A is at the leading edge.

Accumulating data indicate that several components of the macroautophagy/autophagy machinery mediate additional functions, which do not depend on autophagosome biogenesis or lysosomal cargo degradation. In this context, we found that the core autophagy protein ATG9A participates in the chemotactic movement of several cell lines, including highly invasive glioblastoma cells. Accordingly, ATG9A-depleted cells are unable to form large and persistent leading-edge protrusions. By the design of an ATG9A-pHluorin construct and TIRF imaging, we established that ATG9A-positive vesicles are targeted toward the migration front, where their exocytosis is synchronized with protrusive activity. We finally demonstrated that ATG9A, through its interaction with clathrin adaptor complexes, controls the delivery of ITGB1 (integrin subunit beta 1) to the migration front and normal adhesion dynamics. Together, our work indicates that ATG9A protein has a wider role than anticipated and constitutes a critical component of vesicular trafficking allowing the expansion of cell protrusions and their anchorage to the extracellular matrix.

The core autophagy protein ATG9A controls dynamics of cell protrusions and directed migration.

Chemotactic migration is a fundamental cellular behavior relying on the coordinated flux of lipids and cargo proteins toward the leading edge. We found here that the core autophagy protein ATG9A plays a critical role in the chemotactic migration of several human cell lines, including highly invasive glioma cells. Depletion of ATG9A protein altered the formation of large and persistent filamentous actin (F-actin)-rich lamellipodia that normally drive directional migration. Using live-cell TIRF microscopy, we demonstrated that ATG9A-positive vesicles are targeted toward the migration front of polarized cells, where their exocytosis correlates with protrusive activity. Finally, we found that ATG9A was critical for efficient delivery of ß1 integrin to the leading edge and normal adhesion dynamics. Collectively, our data uncover a new function for ATG9A protein and indicate that ATG9A-positive vesicles are mobilized during chemotactic stimulation to facilitate expansion of the lamellipodium and its anchorage to the extracellular matrix.

Hyaluronic acid-based hydrogels loaded with chemoattractant and anticancer drug - new formulation for attracting and tackling glioma cells.

Over the last few years, significant interest has emerged in the development of localised therapeutic strategies for the treatment of glioblastoma (GBM). The concept of attracting and trapping residual tumour cells within a confined area to facilitate their eradication has developed progressively. Herein, we propose a new design of hyaluronic acid-based hydrogel which can be utilized as a matrix containing a soluble chemoattractant to attract residual glioma cells and chemotherapeutic agents to eradicate them in a less invasive and more efficient way compared to the currently available methods. Hydrogels were prepared at different crosslinking densities, e.g. low and high density, by crosslinking hyaluronic acid with various concentrations of adipic acid dihydrazide and U87MG GBM cell morphology, survival and CD44 expression were evaluated. As a proof-of-concept, hydrogels were loaded with a small peptide chemokine, human urotensin II (hUII), and the migration and survival of U87MG GBM cells were studied. Chemoattractant-containing hydrogels were also loaded with chemotherapeutic drugs to promote cell death in culture. The results showed that U87MG cells were able to invade the hydrogel network and to migrate in response to the chemoattractant hUII. In addition, in static condition, hydrogels loaded with doxorubicin demonstrated significant cytotoxicity leading to less than 80% U87MG cell viability after 48 hours when compared to the control sample. In addition, in in vitro invasive assays, it was originally shown that the chemoattractant effect of hUII can be effective before the cytotoxic action of doxorubicin on the U87MG cells trapped in the hydrogel. Our results provide new insights into a promising approach which can be readily translated in vivo for the treatment of one of the most devastating brain tumours.

PAK3 is a key signature gene of the glioma proneural subtype and affects its proliferation, differentiation and growth.

PURPOSE: Gliomas are the most lethal adult primary brain cancers. Recent advances in their molecular characterization have contributed to a better understanding of their pathophysiology, but there is still a need to identify key genes controling glioma cell proliferation and differentiation. The p21-activated kinases PAK1 and PAK2 play essential roles in cell division and brain development and are well-known oncogenes. In contrast, the role of PAK3 in cancer is poorly understood. It is known, however, that this gene is involved in brain ontogenesis and has been identified as a gene of the proneural subtype signature in glioblastomas. METHODS: To better understand the role of PAK kinases in the pathophysiology of gliomas, we conducted expression analyses by querying multiple gene expression databases and analyzing primary human glioma samples. We next studied PAK3 expression upon differentiation in patient-derived cell lines (PDCLs) and the effects of PAK3 inhibition by lentiviral-mediated shRNA on glioma cell proliferation, differentiation and tumor growth. RESULTS: We show that contrary to PAK1 and PAK2, high PAK3 expression positively correlates with a longer survival of glioma patients. We also found that PAK3 displays differential expression patterns between glioma sub-groups with a higher expression in 1p/19q-codeleted oligodendrogliomas, and is highly expressed in tumors and PDCLs of the proneural subtype. In PDCLs, high PAK3 expression negatively correlated with proliferation and positively correlated with neuronal differentiation. Inhibition of PAK3 expression increased PDCL proliferation and glioma tumor growth in nude mice. CONCLUSIONS: Our results indicate that PAK3 plays a unique role among PAKs in glioma development and may represent a potential therapeutic target.

The Prostate Cancer Therapy Enzalutamide Compared with Abiraterone Acetate/Prednisone Impacts Motivation for Exploration, Spatial Learning and Alters Dopaminergic Transmission in Aged Castrated Mice.

Cognitive side effects after cancer treatment threatening quality of life (QoL) constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are examples of next-generation therapy (NGT) administered to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment were reported. We developed a behavioral 17 months-aged and castrated mouse model receiving per os AAP or ENZ for 5 days per week for six consecutive weeks. ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH+-DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus highlighted ENZ-induced dopaminergic regulation within the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN+-neurons in the dorsal hippocampus. The consequences of the mCRPC treatment ENZ on aged castrated mouse motivation to exploration and cognition should make reconsider management strategy of elderly prostate cancer patients.

Targeting the Urotensin II/UT G Protein-Coupled Receptor to Counteract Angiogenesis and Mesenchymal Hypoxia/Necrosis in Glioblastoma.

Glioblastomas (GBMs) are the most common primary brain tumors characterized by strong invasiveness and angiogenesis. GBM cells and microenvironment secrete angiogenic factors and also express chemoattractant G protein-coupled receptors (GPCRs) to their advantage. We investigated the role of the vasoactive peptide urotensin II (UII) and its receptor UT on GBM angiogenesis and tested potential ligand/therapeutic options based on this system. On glioma patient samples, the expression of UII and UT increased with the grade with marked expression in the vascular and peri-necrotic mesenchymal hypoxic areas being correlated with vascular density. In vitro human UII stimulated human endothelial HUV-EC-C and hCMEC/D3 cell motility and tubulogenesis. In mouse-transplanted Matrigel sponges, mouse (mUII) and human UII markedly stimulated invasion by macrophages, endothelial, and smooth muscle cells. In U87 GBM xenografts expressing UII and UT in the glial and vascular compartments, UII accelerated tumor development, favored hypoxia and necrosis associated with increased proliferation (Ki67), and induced metalloproteinase (MMP)-2 and -9 expression in Nude mice. UII also promoted a "tortuous" vascular collagen-IV expressing network and integrin expression mainly in the vascular compartment. GBM angiogenesis and integrin αvß3 were confirmed by in vivo 99mTc-RGD tracer imaging and tumoral capture in the non-necrotic area of U87 xenografts in Nude mice. Peptide analogs of UII and UT antagonist were also tested as potential tumor repressor. Urotensin II-related peptide URP inhibited angiogenesis in vitro and failed to attract vascular and inflammatory components in Matrigel in vivo. Interestingly, the UT antagonist/biased ligand urantide and the non-peptide UT antagonist palosuran prevented UII-induced tubulogenesis in vitro and significantly delayed tumor growth in vivo. Urantide drastically prevented endogenous and UII-induced GBM angiogenesis, MMP, and integrin activations, associated with GBM tumoral growth. These findings show that UII induces GBM aggressiveness with necrosis and angiogenesis through integrin activation, a mesenchymal behavior that can be targeted by UT biased ligands/antagonists.

TRP Channels in Brain Tumors.

Malignant glioma including glioblastoma (GBM) is the most common group of primary brain tumors. Despite standard optimized treatment consisting of extensive resection followed by radiotherapy/concomitant and adjuvant therapy, GBM remains one of the most aggressive human cancers. GBM is a typical example of intra-heterogeneity modeled by different micro-environmental situations, one of the main causes of resistance to conventional treatments. The resistance to treatment is associated with angiogenesis, hypoxic and necrotic tumor areas while heterogeneity would accumulate during glioma cell invasion, supporting recurrence. These complex mechanisms require a focus on potential new molecular actors to consider new treatment options for gliomas. Among emerging and underexplored targets, transient receptor potential (TRP) channels belonging to a superfamily of non-selective cation channels which play critical roles in the responses to a number of external stimuli from the external environment were found to be related to cancer development, including glioma. Here, we discuss the potential as biological markers of diagnosis and prognosis of TRPC6, TRPM8, TRPV4, or TRPV1/V2 being associated with glioma patient overall survival. TRPs-inducing common or distinct mechanisms associated with their Ca2+-channel permeability and/or kinase function were detailed as involving miRNA or secondary effector signaling cascades in turn controlling proliferation, cell cycle, apoptotic pathways, DNA repair, resistance to treatment as well as migration/invasion. These recent observations of the key role played by TRPs such as TRPC6 in GBM growth and invasiveness, TRPV2 in proliferation and glioma-stem cell differentiation and TRPM2 as channel carriers of cytotoxic chemotherapy within glioma cells, should offer new directions for innovation in treatment strategies of high-grade glioma as GBM to overcome high resistance and recurrence.

Stabilization Strategies for Linear Minigastrin Analogues: Further Improvements via the Inclusion of Proline into the Peptide Sequence.

Minigastrin (MG) analogues, known for their high potential to target cholecystokinin-2 receptor (CCK2R) expressing tumors, have limited clinical applicability due to low enzymatic stability. By introducing site-specific substitutions within the C-terminal receptor-binding sequence, reduced metabolization and improved tumor targeting can be achieved. In this work, the influence of additional modification within the N-terminal sequence has been explored. Three novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated CCK2R ligands with proline substitution at different positions were synthesized. Substitution did not affect CCK2R affinity, and the conjugates labeled with indium-111 and lutetium-177 showed a high enzymatic stability in different incubation media as well as in vivo (57-79% intact radiopeptide in blood of BALB/c mice at 1 h p.i.) combined with enhanced tumor uptake (29-46% IA/g at 4 h in xenografted BALB/c nude mice). The inclusion of Pro contributes significantly to the development of CCK2R ligands with optimal targeting properties for application in targeted radiotherapy.

Postoperative fatigue after day surgery: prevalence and risk factors. A prospective observational study.

BACKGROUND: Postoperative fatigue (POF) is a major cause of rehabilitation failure after surgery. POF is a complication that could negatively affect outpatients but to date no study has specifically investigated POF at home after day surgery. The objective of this study was to assess early and late POF and risk factors for POF after day surgery. METHODS: This prospective single center observational study was conducted from October 2015 to January 2016. All patients scheduled for day surgery under general or regional anesthesia were assessed for eligibility. The primary endpoint was the prevalence of early POF (Day 1), defined by a VAS measurement of fatigue greater than three (on a scale of 0 to 10). Secondary endpoints were the prevalence of late POF (Day 7), the prevalence of severe POF (VAS> 6) at D1 and D7 and risk factors for preoperative fatigue, and for early and late POF. RESULTS: Among 348 patients, the prevalence of early and late POF was 37% (95% CI: 32-42) and 16% (95% CI: 12.1-19.9), respectively. The prevalence of severe POF was 9% at D1 and 3% at D7. The main risk factor for early POF was postoperative pain (P<0.01). CONCLUSIONS: This work suggests that early and late POF are common after day surgery but that severe POF is rare. Postoperative pain is the main risk factors for the early POF. The optimized management of postoperative pain could probably decrease the prevalence of POF after day surgery.

Development of Novel 111-In-Labelled DOTA Urotensin II Analogues for Targeting the UT Receptor Overexpressed in Solid Tumours.

Overexpression of G protein-coupled receptors (GPCRs) in tumours is widely used to develop GPCR-targeting radioligands for solid tumour imaging in the context of diagnosis and even treatment. The human vasoactive neuropeptide urotensin II (hUII), which shares structural analogies with somatostatin, interacts with a single high affinity GPCR named UT. High expression of UT has been reported in several types of human solid tumours from lung, gut, prostate, or breast, suggesting that UT is a valuable novel target to design radiolabelled hUII analogues for cancer diagnosis. In this study, two original urotensinergic analogues were first conjugated to a DOTA chelator via an aminohexanoic acid (Ahx) hydrocarbon linker and then -hUII and DOTA-urantide, complexed to the radioactive metal indium isotope to successfully lead to radiolabelled DOTA-Ahx-hUII and DOTA-Ahx-urantide. The 111In-DOTA-hUII in human plasma revealed that only 30% of the radioligand was degraded after a 3-h period. DOTA-hUII and DOTA-urantide exhibited similar binding affinities as native peptides and relayed calcium mobilization in HEK293 cells expressing recombinant human UT. DOTA-hUII, not DOTA-urantide, was able to promote UT internalization in UT-expressing HEK293 cells, thus indicating that radiolabelled 111In-DOTA-hUII would allow sufficient retention of radioactivity within tumour cells or radiolabelled DOTA-urantide may lead to a persistent binding on UT at the plasma membrane. The potential of these radioligands as candidates to target UT was investigated in adenocarcinoma. We showed that hUII stimulated the migration and proliferation of both human lung A549 and colorectal DLD-1 adenocarcinoma cell lines endogenously expressing UT. In vivo intravenous injection of 111In-DOTA-hUII in C57BL/6 mice revealed modest organ signals, with important retention in kidney. 111In-DOTA-hUII or 111In-DOTA-urantide were also injected in nude mice bearing heterotopic xenografts of lung A549 cells or colorectal DLD-1 cells both expressing UT. The observed significant renal uptake and low tumour/muscle ratio (around 2.5) suggest fast tracer clearance from the organism. Together, DOTA-hUII and DOTA-urantide were successfully radiolabelled with 111Indium, the first one functioning as a UT agonist and the second one as a UT-biased ligand/antagonist. To allow tumour-specific targeting and prolong body distribution in preclinical models bearing some solid tumours, these radiolabelled urotensinergic analogues should be optimized for being used as potential molecular tools for diagnosis imaging or even treatment tools.

Potential Effect of Immunotherapy Agents on Cognitive Function in Cancer Patients.

A paradigm shift is occurring in cancer therapy, where instead of targeting tumor cells, immunotherapy agents (IA) target the immune system to overcome cancer tolerance and to stimulate an antitumor immune response. IA using immune checkpoint inhibitors (CPI) or chimeric antigen receptor T-cells have emerged as the most encouraging approaches to treat cancer patients. CPI are reported to induce moderate-to-severe neurologic immune-related adverse events in less than 1% of patients, whereas chimeric antigen receptor T-cell therapy is associated with frequent neurological toxicities that can be severe or even fatal. Cognitive difficulties have been described following chemotherapy and targeted therapy, but not specifically explored in patients receiving IA. The aim of this review is to establish a picture of the first published studies suggesting some biological and physiopathological effects of IA on cognitive functions among cancer patients. The first results originate from a preclinical study evaluating the role of CPI associated with peripheral radiation on cognitive dysfunction and the recent discovery of the central nervous lymphatic system allowing leukocytes to penetrate the central nervous system. Evaluating possible side effects of IA on cognitive function will be an important challenge for future clinical trials and for better understanding the underlying mechanisms through preclinical animal models.

Urantide Improves Cardiac Function, Modulates Systemic Cytokine Response, and Increases Survival in A Murine Model of Endotoxic Shock.

INTRODUCTION: Urotensin II is a potent vasoactive peptide activating the the G protein-coupled urotensin II receptor UT, and is involved in systemic inflammation and cardiovascular functions. The aim of our work was to study the impact of the UT antagonist urantide on survival, systemic inflammation, and cardiac function during endotoxic shock. METHODS: C57Bl/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) and then randomized to be injected either by urantide or NaCl 0.9% 3, 6, and 9 h (H3, H6, H9) after LPS. The effect of urantide on the survival rate, the levels of cytokines in plasma at H6, H9, H12, the expression level of nuclear factor-kappa B (NF-κB-p65) in liver and kidney (at H12), and the cardiac function by trans-thoracic echocardiography from H0 to H9 was evaluated. RESULTS: Urantide treatment improved survival (88.9% vs. 30% on day 6, P < 0.05). This was associated with changes in cytokine expression: a decrease in IL-6 (2,485 [2,280-2,751] pg/mL vs. 3,330 [3,119-3,680] pg/mL, P < 0.01) at H6, in IL-3 (1.0 [0.40-2.0] pg/mL vs. 5.8 [3.0-7.7] pg/mL, P < 0.01), and IL-1ß (651 [491-1,135] pg/mL vs. 1,601 [906-3,010] pg/mL, P < 0.05) at H12 after LPS administration. Urantide decreased the proportion of cytosolic NF-κB-p65 in liver (1.3 [0.9-1.9] vs. 3.2 [2.3-4], P < 0.01) and kidney (0.3 [0.3-0.4] vs. 0.6 [0.5-1.1], P < 0.01). Urantide improved cardiac function (left ventricular fractional shortening: 24.8 [21.5-38.9] vs. 12.0 [8.7-17.6] %, P < 0.01 and cardiac output: 30.3 [25.9-39.8] vs. 15.1 [13.0-16.9] mL/min, P < 0.0001). CONCLUSION: These results show a beneficial curative role of UT antagonism on cytokine response (especially IL-3), cardiac dysfunction, and survival during endotoxic shock in mice, highlighting a potential new therapeutic target for septic patients.

How to assess and manage cognitive impairment induced by treatments of non-central nervous system cancer.

A number of neurotoxicity associated with oncological treatments has been reported in non-central nervous system cancers. An expert group presents the state of the art and a guide to help the choice of appropriated tools to assess patient cognition in studies on oncology and neurobehavior in animal models. In addition, current cognitive rehabilitation programs currently under evaluation are also discussed. Cognitive assessments in oncology depend on the research question, study design, cognitive domains, patients' characteristics, psychometric properties of the tests, and whether the tests are supervised or not by a neuropsychologist. Batteries of electronic tests can be proposed, but several of them are characterized by weak psychometric developments. In order to improve the comprehension on the impact of cancer treatments on cognition, new animal models are in development, and would in the future include non-human primate models. By bringing together the skills and practices of oncologists, neurologists, neuropsychologists, neuroscientists, we propose a series of specific tools and tests that accompany the cognitive management of non-CNS cancer patients.