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Linear bosonic modes offer a hardware-efficient alternative for quantum information processing but require access to some nonlinearity for universal control. The lack of nonlinearity in photonics has led to encoded measurement-based quantum computing, which relies on linear operations but requires access to resourceful ('nonlinear') quantum states, such as cubic phase states. In contrast, superconducting microwave circuits offer engineerable nonlinearities but suffer from static Kerr nonlinearity. Here, we demonstrate universal control of a bosonic mode composed of a superconducting nonlinear asymmetric inductive element (SNAIL) resonator, enabled by native nonlinearities in the SNAIL element. We suppress static nonlinearities by operating the SNAIL in the vicinity of its Kerr-free point and dynamically activate nonlinearities up to third order by fast flux pulses. We experimentally realize a universal set of generalized squeezing operations, as well as the cubic phase gate, and exploit them to deterministically prepare a cubic phase state in 60 ns. Our results initiate the experimental field of polynomial quantum computing, in the continuous-variables notion originally introduced by Lloyd and Braunstein., (© 2024. The Author(s).)

Chimeric antigen receptor (CAR)-T cell therapies have shown tremendous results against various hematologic cancers. Prior to cell infusion, a host preconditioning regimen is required to achieve lymphodepletion and improve CAR-T cell pharmacokinetic exposure, leading to greater chances of therapeutic success. To better understand and quantify the impact of the preconditioning regimen, we built a population-based mechanistic pharmacokinetic-pharmacodynamic model describing the complex interplay between lymphodepletion, host immune system, homeostatic cytokines, and pharmacokinetics of UCART19, an allogeneic product developed against CD19 + B cells. Data were collected from a phase I clinical trial in adult relapsed/refractory B-cell acute lymphoblastic leukemia and revealed three different UCART19 temporal patterns: (i) expansion and persistence, (ii) transient expansion with subsequent rapid decline, and (iii) absence of observed expansion. On the basis of translational assumptions, the final model was able to capture this variability through the incorporation of IL-7 kinetics, which are thought to be increased owing to lymphodepletion, and through an elimination of UCART19 by host T cells, which is specific to the allogeneic context. Simulations from the final model recapitulated UCART19 expansion rates in the clinical trial, confirmed the need for alemtuzumab to observe UCART19 expansion (along with fludarabine cyclophosphamide), quantified the importance of allogeneic elimination, and suggested a high impact of multipotent memory T-cell subpopulations on UCART19 expansion and persistence. In addition to supporting the role of host cytokines and lymphocytes in CAR-T cell therapy, such a model could help optimizing the preconditioning regimens in future clinical trials., Significance: A mathematical mechanistic pharmacokinetic/pharmacodynamic model supports and captures quantitatively the beneficial impact of lymphodepleting patients before the infusion of an allogeneic CAR-T cell product. Mediation through IL-7 increase and host T lymphocytes decrease is underlined, and the model can be further used to optimize CAR-T cell therapies lymphodepletion regimen., Competing Interests: T. Derippe reports grants from Servier during the conduct of the study; grants from Servier outside the submitted work. S. Fouliard reports personal fees from Servier during the conduct of the study. I. Marchiq reports other from Allogene Therapeutics during the conduct of the study; and I. Marchiq is an employee of Servier. S. Dupouy reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. M. Almena-Carrasco reports personal fees from Institut de Rechercher International Servier outside the submitted work. J. Geronimi reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. D.E. Mager reports grants from Servier during the conduct of the study. No disclosures were reported by the other author., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Background: UCART19 is an "off-the-shelf" genome-edited anti-CD19 chimeric antigen receptor (CAR)-T cell product, manufactured from unrelated healthy donor cells., Methods: UCART19 was administered to 25 adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) in the CALM trial. All patients underwent lymphodepletion with fludarabine and cyclophosphamide ± alemtuzumab and received one of three ascending doses of UCART19. Given the allogeneic nature of UCART19, we analyzed the impact of lymphodepletion, HLA disparities, and host immune system reconstitution on its kinetics, along with other factors known to affect autologous CAR-T cell clinical pharmacology., Results: Responder patients (12/25) had higher UCART19 expansion ( C max ) and exposure (AUCT last ) than nonresponders (13/25), as measured by transgene levels in peripheral blood. The persistence of CAR + T cells did not exceed 28 days in 10/25 patients and lasted beyond 42 days in 4/25. No significant correlation was found between UCART19 kinetics and administered cell dose, patient and product characteristics or HLA disparities. However, the number of prior lines of therapy and absence of alemtuzumab negatively impacted UCART19 expansion and persistence. Alemtuzumab exposure positively affected IL7 and UCART19 kinetics, while negatively correlating with host T lymphocyte AUC 0-28 ., Conclusions: UCART19 expansion is a driver of response in adult patients with R/R B-ALL. These results shed light on the factors associated with UCART19 kinetics, which remain highly affected by the impact of alemtuzumab on IL7 and host-versus-graft rejection., Significance: First description of the clinical pharmacology of a genome-edited allogeneic anti-CD19 CAR-T cell product showing the crucial role of an alemtuzumab-based regimen in sustaining UCART19 expansion and persistence through increased IL7 availability and decreased host T lymphocyte population., Competing Interests: S. Dupouy reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. I. Marchiq reports other from Allogene Therapeutics during the conduct of the study; and I. Marchiq is an employee of Servier. T. Derippe reports grants from Servier during the conduct of the study; grants from Servier outside the submitted work. M. Almena-Carrasco reports personal fees from Servier Laboratoires and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier Laboratoires outside the submitted work. S. Fouliard reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. J. Geronimi reports personal fees from Servier and other from Allogene Therapeutics during the conduct of the study; personal fees from Servier outside the submitted work. C. Graham reports grants from Servier during the conduct of the study. N. Jain reports grants, personal fees, and non-financial support from Servier during the conduct of the study; grants, personal fees, and non-financial support from Cellectis, Precision Biosciences, Abbvie, Genentech, Loxo Oncology, Fate Therapeutics; grants from Takeda outside the submitted work. M.V. Maus reports other from 2Seventy Bio outside the submitted work; in addition, M.V. Maus has a patent to Patents in CAR T cells for multiple indications pending; and M.V. Maus is an inventor on patents related to adoptive cell therapies, held by Massachusetts General Hospital (some licensed to Promab) and University of Pennsylvania (some licensed to Novartis). M.V. Maus holds Equity in 2SeventyBio, Century Therapeutics, Neximmune, Oncternal, and TCR2 and has served as a consultant for multiple companies involved in cell therapies; board of directors: 2Seventy Bio; M.V. Maus is a consultant for: Adaptimmune, Agenus, Allogene, Arcellx, Astellas, AstraZeneca, Atara, Bayer, BMS, Cabaletta Bio (SAB), Cellectis (SAB), CRISPR therapeutics, Genocea, In8bio (SAB), Intellia, GSK, Kite Pharma, Micromedicine/BendBio, Neximmune, Novartis, Oncternal, Sanofi, TCR2 (SAB), Tmunity, and WindMIL (SAB); M.V. Maus has had Grant/Research support : CRISPR therapeutics, Kite Pharma, Servier, Novartis; speaker's bureau: none. M. Mohty reports grants and personal fees from Jazz, Janssen, Sanofi; personal fees from Amgen, Takeda, Pfizer, Adaptive, Novartis, Astellas, GSK, Oncopeptides, and BMS outside the submitted work. N. Boissel reports personal fees from SERVIER during the conduct of the study; grants and personal fees from AMGEN; personal fees from Pfizer, Gilead, and Novartis outside the submitted work. T. Teshima reports grants from Sanofi, Chugai, Astellas, Teijin Pharma, Fuji Pharma, Nippon Shinyaku; personal fees from Merck Sharp & Dohme, Pfizer, Bristol-Myers Squibb; grants and personal fees from Kyowa Kirin; non-financial support from Janssen; grants, personal fees, and non-financial support from Novartis, and personal fees from Takeda outside the submitted work. K. Kato reports grants from Kyowa-Kirin, Novartis, Chugai, Takeda, AbbVie, Eisai, Janssen, Bristol-Myers Squibb, Ono, and Daiichi Sankyo during the conduct of the study. R. Benjamin reports grants from Servier and Allogene during the conduct of the study. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Background: The prognosis for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia remains poor. UCART19, an allogeneic genome-edited anti-CD19 chimeric antigen receptor (CAR) T-cell product derived from healthy donors and available for immediate clinical use, offers a potential therapeutic option for such patients. The CALM trial is a first-in-human study evaluating the safety and antileukaemic activity of UCART19 in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia., Methods: This phase 1, open-label study was conducted at eight centres across France, the UK, the USA, and Japan. Adult patients aged 16-70 years with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukaemia who had morphological relapse or a minimal residual disease level of at least 1 × 10 -3 and had exhausted standard treatment options were enrolled in the study, which comprised a dose-escalation phase of up to three UCART19 doses followed by a safety expansion phase. Patients underwent lymphodepletion with fludarabine (30 mg/m 2 per day intravenously for 3 days) and cyclophosphamide (500 mg/m 2 per day intravenously for 3 days) with or without alemtuzumab (1 mg/kg or 40 mg or 60 mg over 5 days) and received UCART19 doses of 6 × 10 6 , 6-8 × 10 7 , or 1·8-2·4 × 10 8 total CAR T cells intravenously, followed by safety evaluation and disease response assessments. The primary endpoint was incidence and severity of adverse events. Secondary endpoints were the overall response rate, duration of response, relapse-free survival, progression-free survival, and overall survival. This trial is registered with ClinicalTrials.gov (NCT02746952) and is complete., Findings: Between Aug 1, 2016, and June 30, 2020, 25 patients were enrolled in the study and treated with UCART19. Median duration of follow-up was 12·8 months (IQR 2·8-24·8). Median age was 37 years (IQR 28-45). 14 (56%) patients were male and 11 (44%) female. 17 (68%) patients were White, two (8%) Black, two (8%) Asian, and four (16%) from other racial or ethnic groups. Three patients developed dose-limiting toxicities (one at each dose level); one had grade 4 cytokine release syndrome and two had grade 4 prolonged cytopenias. Grade 3 or higher cytokine release syndrome was reported in six (24%) patients and grade 3 or higher neurological toxicity in one (4%) patient. Grade 3 or higher infections occurred in seven (28%) patients, and grade 4 prolonged cytopenia in four (16%) patients. Two (8%) patients developed grade 1 acute cutaneous graft-versus-host disease. 14 patients died, nine from progressive disease and five from infections or other complications, of which four were considered to be related to UCART19 or lymphodepletion, or both. After a median of follow-up of 12·8 months (IQR 2·8-24·8), overall response rate was 48% (95% CI 28-69; 12 of 25 patients), duration of response and median relapse-free survival were 7·4 months (95% CI 1·8 to not calculable), progression-free survival was 2·1 months (95% CI 1·2-2·8), and overall survival was 13·4 months (95% CI 4·8-23·0)., Interpretation: UCART19 had a manageable safety profile, and showed evidence of antileukaemic activity in heavily pretreated adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. This study shows that allogeneic off-the-shelf CAR T cells can be used safely to treat patients with relapsed B-cell acute lymphoblastic leukaemia., Funding: Servier., Competing Interests: Declaration of interests RB received research funding from Servier and Allogene and has participated in advisory boards for Kite/Gilead, Novartis, Celgene/Bristol-Myers Squibb, Cellectis, and Enara Bio. NJ reports grants and personal fees from Servier during the conduct of the study; grants, personal fees, and non-financial support from Pharmacyclics, AstraZeneca, Genentech, Verastem, Pfizer, AbbVie, ADC Therapeutics, Precision Biosciences, and Adaptive Biotechnologies; personal fees and non-financial support from Janssen; and grants and non-financial support from Bristol-Myers Squib, Celgene, Seattle Genetics, Incyte, and Cellectis, outside the submitted work. MVM is an inventor on patents related to adoptive cell therapies held by Massachusetts General Hospital and the University of Pennysylvania (some of which are licensed to Novartis), holds equity in TCR2 and Century Therapeutics, and has served as a consultant for multiple companies involved in cell therapies. NB, CG, and AJ received research funding from Servier. DY reports grants and non-financial support from Servier during the conduct of the study, and non-financial support from Amgen and personal fees from Pfizer, outside the submitted work. MK reports grants and other from AbbVie, F. Hoffman La-Roche, Stemline Therapeutics, Forty-Seven, and Genentech; grants from Eli Lilly, Cellectis, Calithera, Ablynx, Agios, Ascentage, Astra Zeneca, Rafael Pharmaceutical, and Sanofi; and honoraria from Reata Pharmaceutical and Janssen outside the submitted work. MK also has a patent US 7,795,305 B2 “CDDO-compounds and combination therapies thereof” with royalties paid to Reata Pharm, a patent “Combination therapy with a mutant IDH1 inhibitor and a BCL-2” licensed to Eli Lilly, and a patent 62/993,166 “Combination of a MCL-1 inhibitor and midostaurin, uses and pharmaceutical compositions thereof” pending to Novartis. MJF has advisory roles with Kite/Gilead, Novartis, Celgene/Bristol-Myers Squibb, Arcellx, and Iovance, and recieves trial support from Kite/Gilead and Novartis. TT reports personal fees from Merck Sharp & Dohme; grants and personal fees from Kyowa Kirin; personal fees from Takeda, Pfizer, and Bristol-Myers Squibb; grants from Chugai, Sanofi, Astellas, Teijin Pharma, Fuji Pharma, Nippon Shinyaku, Japan Society for the Promotion of Science KAKENHI (17H04206), and The Center of Innovation Program from Japan Science and Technology Agency; non-financial support from Janssen; and grants, personal fees, and non-financial support from Novartis, outside the submitted work. KK reports grants and personal fees from AbbVie, Chugai, Eisai, Janssen, Novartis, Daiichi Sankyo, Takeda, and Kyowa-Kirin, and personal fees from AstraZeneca, Celgene, Ono, MSD, Mundi, Dainippon-Sumitomo, and Bristol-Myers Squibb, outside the submitted work. FBo, FBi, IM, SD, MA-C, MP, and SF are employees of Servier. SB and AG-B were previous employees of Servier. EB reports personal fees from Novartis, Astellas, Alexion, Jazz Pharmaceuticals, and Gilead outside the submitted work. MM reports grants and personal fees from Sanofi and Jazz Pharmaceuticals; personal fees from Janssen, Celgene, Bristol-Myers Squibb, Takeda, and Amgen; and grants from Roche, outside the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Genome-edited donor-derived allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia., Methods: We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1-2·3 × 10 6 cells per kg and adults received UCART19 doses of 6 × 10 6 cells, 6-8 × 10 7 cells, or 1·8-2·4 × 10 8 cells in a dose-escalation study. The primary outcome measure was adverse events in the period between first infusion and data cutoff. These studies were registered at ClinicalTrials.gov, NCT02808442 and NCT02746952., Findings: Between June 3, 2016, and Oct 23, 2018, seven children and 14 adults were enrolled in the two studies and received UCART19. Cytokine release syndrome was the most common adverse event and was observed in 19 patients (91%); three (14%) had grade 3-4 cytokine release syndrome. Other adverse events were grade 1 or 2 neurotoxicity in eight patients (38%), grade 1 acute skin graft-versus-host disease in two patients (10%), and grade 4 prolonged cytopenia in six patients (32%). Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent cytokine release syndrome and one from pulmonary haemorrhage in a patient with persistent cytopenia. 14 (67%) of 21 patients had a complete response or complete response with incomplete haematological recovery 28 days after infusion. Patients not receiving alemtuzumab (n=4) showed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%., Interpretation: These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable., Funding: Servier., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background/objective: Performances on spatial decision eye-tracking tasks are known to be impaired in patients with moderate Alzheimer's disease (AD), but the clinical relevance of this deficit during earlier stages of AD remains unclear., Methods: This study recruited patients with amnestic mild cognitive impairment (aMCI, prodromal AD), patients with mild AD, and age-matched controls from three French memory clinics. Participants' ability to make spatial judgments and decisions was assessed with an eye-tracking system, and cognitive performance on conventional neuropsychological tests was evaluated., Results: We enrolled 26 controls, 25 aMCI patients (median Mini-Mental State Exam [MMSE] 26), and 23 mild-AD patients (median MMSE 23). Patients with mild AD had higher error rates on the spatial decision task than aMCI patients and controls (32.4% versus 23.5%; p < 0.01 and 32.4% versus 22.2%; p < 0.05, respectively), but there were no differences among the groups in anticipation rate or the percentage of express saccades. Additionally, error rates on the spatial decision task were inversely correlated with performance on visual memory tests (immediate and delayed recall on the DMS- 48: r =-0.44, p = 0.0019 and r =-0.43, p = 0.0020, respectively), semantic fluency (r =-0.44, p = 0.0016), and global cognition (MMSE: r =-0.44, p = 0.0019). Performance on the spatial decision task was not correlated with anti-saccades, processing speed, or attentional performance., Conclusions: Patients with mild AD made more errors on a spatial decision task than aMCI patients and controls. We hypothesize that impaired visuospatial judgment may explain these results and distinguish aMCI patients from mild AD patients.

Saccade alterations are potential early signs of Alzheimer's disease. However, uncertainty persists in how early and reliably automated saccade recording systems detect impairments. This multicenter pathophysiological case-control transversal study explored saccade execution in carefully diagnosed amnestic mild cognitive impairment patients fulfilling research criteria for prodromal Alzheimer's disease (n = 29), as compared to both aged-matched mild Alzheimer's disease patients (n = 23) and controls (n = 27). Auto-coded saccades from horizontal (gap) vertical (step) stimulus elicited pro-saccades, and anti-saccade (gap) tasks were compared across the 3 groups. Mild cognitive impairment patients committed significantly more anti-saccade errors compared to controls (46.9 versus 24.3%, p < 0.001). Conventional analyses of the auto-coded stimulus elicited saccades parameters did not distinguish the amnestic mild cognitive impairment from controls or the mild Alzheimer's disease group. However, an offline analysis of manually coded saccade latencies, using resampling statistics did reveal subtle differences among the groups. Analysis of the manually coded data revealed that the mild Alzheimer's disease group had a reliably larger self-corrected error-rate than in amnestic mild cognitive impairment and controls (p = 0.003). Analysis of the manually coded saccade latencies, using more sensitive lognormal bootstrap analysis revealed a continuum, from amnestic mild cognitive impairment to mild Alzheimer's disease, of an increased severity of impaired inhibition of stimulus elicited saccades and correct voluntary saccade initiation. Anti-saccade error rates and psychometric measures of executive and several other cognitive functions were moderately and negatively correlated. Overall, inhibitory impairments in stimulus elicited saccades, characteristic of Alzheimer's disease, may be detected early in presumed prodromal patients using a simple, automated anti-saccade task.

The purpose of the study was to evaluate the frequency of restless legs syndrome in 30 patients with multiple system atrophy. Eight patients complained from restless legs syndrome, their severity score was 19.4 ± 4.1. Pittsburgh Sleep Quality Index scores were significantly higher in patients with restless legs syndrome than those without (9.3 ± 3.7 vs. 4.8 ± 2.9, p = 0.00165). Periodic limb movements were found in 75% of patients with restless legs syndrome. Restless legs syndrome is more prevalent in multiple system atrophy as compared to the acknowledged prevalence in the general population.

A present challenge in breast oncology research is to identify therapeutical targets which could impact tumor progression. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in 20% of breast cancers, and NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in invasive breast carcinomas. Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here, we depict the cellular mechanisms activated by NTS, and contributing to breast cancer cell aggressiveness. We show that neurotensin (NTS) and its high affinity receptor (NTSR1) contribute to the enhancement of experimental tumor growth and metastasis emergence in an experimental mice model. This effect ensued following EGFR, HER2, and HER3 over-expression and autocrine activation and was associated with an increase of metalloproteinase MMP9, HB-EGF and Neuregulin 2 in the culture media. EGFR over expression ensued in a more intense response to EGF on cellular migration and invasion. Accordingly, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, as well as metformin, reduced the tumor growth of cells overexpressing NTS and NTSR1. All cellular effects, such as adherence, migration, invasion, altered by NTS/NTSR1 were abolished by a specific NTSR1 antagonist. A strong statistical correlation between NTS-NTSR1-and HER3 (p< 0.0001) as well as NTS-NTSR1-and HER3- HER2 (p< 0.001) expression was found in human breast tumors. Expression of NTS/NTSR1 on breast tumoral cells creates a cellular context associated with cancer aggressiveness by enhancing epidermal growth factor receptor activity. We propose the use of labeled NTS/NTSR1 complexes to enlarge the population eligible for therapy targeting HERs tyrosine kinase inhibitor or HER2 overexpression.

Alterations in the signaling pathways of epidermal growth factor receptors (HERs) are associated with tumor aggressiveness. Neurotensin (NTS) and its high affinity receptor (NTSR1) are up regulated in 60% of lung cancers. In a previous clinical study, NTSR1 overexpression was shown to predict a poor prognosis for 5 year overall survival in a selected population of stage I lung adenocarcinomas treated by surgery alone. In a second study, shown here, the frequent and high expression of NTSR1 was correlated with a pejorative prognosis in 389 patients with stage I to III lung adenocarcinoma, and was an independent prognosis marker. Interactions between NTS and NTSR1 induce pro-oncogenic biological effects associated with neoplastic processes and tumor progression. Here we highlight the cellular mechanisms activated by Neurotensin (NTS) and its high affinity receptor (NTSR1) contributing to lung cancer cell aggressiveness. We show that the NTS autocrine and/or paracrine regulation causes EGFR, HER2, and HER3 over-expression and activation in lung tumor cells. The EGFR and HER3 autocrine activation is mediated by MMP1 activation and EGF "like" ligands (HB-EGF, Neuregulin 1) release. By establishing autocrine and/or paracrine NTS regulation, we show that tumor growth is modulated according to NTS expression, with a low growth rate in those tumors that do not express NTS. Accordingly, xenografted tumors expressing NTS and NTSR1 showed a positive response to erlotinib, whereas tumors void of NTSR1 expression had no detectable response. This is consistent with the presence of a NTS autocrine loop, leading to the sustained activation of EGFR and responsible for cancer aggressiveness. We propose the use of NTS/NTSR1 tumor expression, as a biomarker for the use of EGFR tyrosine kinase inhibitors in patients lacking EGFR mutation.

We here assess limbic and orbitofrontal control in 20 patients with essential tremor (ET) and 18 age-matched healthy controls using the Ekman Facial Emotion Recognition Task and the IOWA Gambling Task. Our results show an inverse relation between facial emotion recognition and tremor severity. ET patients also showed worse performance in joy and fear recognition, as well as subtle abnormalities in risk detection, but these differences did not reach significance after correction for multiple testing.

Objective: To assess the diagnostic accuracy of portable polygraphy (PG) for the detection of sleep apnea (SA) in multiple system atrophy (MSA)., Methods: Thirty consecutive patients with probable MSA underwent PG (overnight recording of nasal flow, thoracic/abdominal movements and pulse oximetry), followed 4 weeks later by full polysomnography (PSG) (reference standard). The accuracy of PG was first assessed using the same threshold as for PSG (apnea-hypopnea index [AHI]≥5), then for all possible AHI thresholds using the area under the receiver operating characteristics (AUROC) curve. Inter-rater reliability of PG was assessed using the kappa coefficient., Results: Among 30 patients enrolled, seven were excluded for technical problems on PG or PSG and 23 were included in the main analysis. Eight out of 23 had an AHI≥5 on PSG. With the same threshold, sensitivity, specificity, positive and negative predictive values of PG for the diagnosis of SA were 87.5% (95% confidence interval: 47-99), 80% (52-96), 70% (35-93) and 92.3% (64-99), respectively. The kappa between PG raters was 0.75 (0.49-1.00) indicating good agreement. The AUROC was 0.93 (0.82-1.00). No association was found between sleep and excessive daytime sleepiness questionnaires and SA., Conclusion: Portable PG seems to be valuable for ruling out SA in MSA., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Simvastatin may improve levodopa-induced dyskinesia through striatal Ras-extracellular signal-regulated kinase pathway modulation., Methods: (1) Six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques were assessed for parkinsonism and dyskinesia severity following acute co-administration of levodopa and simvastatin (0, 1.5, 3 and 6 mg/kg). (2) A "n-of-1" design randomized, placebo-controlled, 3 cross-over trial was then conducted in 10 Parkinson's disease patients with troublesome dyskinesia. The primary endpoint was a 7-point scale rating subjective discomfort caused by troublesome dyskinesia. Secondary endpoints related to dyskinesia severity and duration and functional impairment, severity and duration of OFF periods, motor scores and investigator- and patient-rated global impressions. (3) The pharmacodynamic variable for both studies consisted in a multiplex analysis of kinase-induced phosphorylation in T and B-lymphocytes by flow cytometry., Results: (1) In the macaque, simvastatin reduced dyskinesia scores (45%), at the dose of 3 mg/kg (2) In the "n-of-1" trial no significant response was observed in the primary end point and all secondary endpoints. No serious adverse events were reported. (3) Simvastatin 3 mg/kg significantly reduce kinase-induced phosphorylation in monkeys but not simvastatin 40 mg in patients., Conclusions: Simvastatin reduced dyskinesia in primates using high doses over 3 mg/kg but the exploratory trial in patients revealed no effect at 40 mg/d suggesting that higher doses, not compatible with a safe prolonged administration, are necessary., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Multiple system atrophy (MSA) has considerable effect on health-related quality of life (Hr-QoL). The aim of this study was to prospectively evaluate Hr-QoL by using the MSA health-related Quality of Life (MSA-QoL) scale., Methods: Evaluation of 100 patients at baseline and after a mean follow-up of 11.5 months was performed. Assessment was made of potential associations with established markers of disease progression. Calculation was performed of sample-size estimates for various effect sizes., Results: MSA-QoL scale scores were less responsive to change than Unified MSA Rating Scale (UMSARS) scores. Responsiveness was largely improved and reasonable sample-size estimates were obtained when limiting the analysis to items with significant change over time., Conclusions: The UMSARS remains the "gold standard" for disease-modifying/neuroprotection trials. An MSA-QoL Change Scale, based on the most responsive items, may become a valuable tool., (Copyright © 2012 Movement Disorder Society.)

Comparing Charles Darwin's account of emotional expression to previous nineteenth-century scientific studies on the same subject, this article intends to locate the exact nature of Darwin's break in his 1872 book (as well as in his earlier notebooks). In contrast to a standard view that approaches this question in the framework of the creationism/evolutionism dichotomy, I argue that Darwin's account distinguishes itself primarily by its distance toward the sentimentalist values and moral hierarchies that were traditionally linked with the study of expression--an attitude that is not an inevitable ingredient of the theory of evolution. However, Darwin's approach also reintroduces another kind of hierarchy in human expression, but one based on attenuation and self-restraint in the exhibition of expressive signs., (© 2011 Wiley Periodicals, Inc.)

A growing challenge in medicine today, is the need to improve the suitability of drug treatments for cancer patients. In this field, biomarkers have become the "flags" to provide additional information in tumor biology. They are a relay between the patient and practitioner and consequently, aid in the diagnosis, providing information for prognosis, or in some cases predicting the response to specific therapies. In addition to being markers, these tumor "flags" can also be major participants in the process of carcinogenesis. Neurotensin receptor 1 (NTSR1) was recently identified as a prognosis marker in breast, lung, and head and neck squamous carcinomas. Neurotensin (NTS) was also shown to exert numerous oncogenic effects involved in tumor growth and metastatic spread. These effects were mostly mediated by NTSR1, making the NTS/NTSR1 complex an actor in cancer progression. In this review, we gather information on the oncogenic effects of the NTS/NTSR1 complex and its associated signaling pathways in order to illuminate its significant role in tumor progression and its potential as a biomarker and a therapeutic target in some tumors., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Purpose: This study aimed to investigate the role of the neurotensin/neurotensin receptor I (NTSR1) complex in non-small cell lung cancer (NSCLC) progression., Experimental Design: The expression of neurotensin and NTSR1 was studied by transcriptome analysis and immunohistochemistry in two series of 74 and 139 consecutive patients with pathologic stage I NSCLC adenocarcinoma. The findings were correlated with clinic-pathologic features. Experimental tumors were generated from the malignant human lung carcinoma cell line A459, and a subclone of LNM35, LNM-R. The role of the neurotensin signaling system on tumor growth and metastasis was investigated by small hairpin RNA-mediated silencing of NTSR1 and neurotensin., Results: Transcriptome analysis carried out in a series of 74 patients showed that the positive regulation of NTSR1 put it within the top 50 genes related with relapse-free survival. Immunohistochemistry revealed neurotensin- and NTSR1-positive staining in 60.4% and 59.7% of lung adenocarcinomas, respectively. At univariate analysis, NTSR1 expression was strongly associated with worse 5-year overall survival rate (P = 0.0081) and relapse-free survival (P = 0.0024). Multivariate analysis showed that patients over 65 years of age (P = 0.0018) and NTSR1 expression (P = 0.0034) were independent negative prognostic factors. Experimental tumor xenografts generated by neurotensin- and NTSR1-silenced human lung cancer cells revealed that neurotensin enhanced primary tumor growth and production of massive nodal metastasis via autocrine and paracrine regulation loops., Conclusion: NTSR1 expression was identified as a potential new prognostic biomarker for surgically resected stage I lung adenocarcinomas, as NTSR1 activation was shown to participate in lung cancer progression.

Malignant pleural mesothelioma is a frequently fatal disease and the impact of available treatments is globally poor. Identification of new prognostic factors would help in the understanding of disease progression and, possibly, patient management. Here, we evaluate the prognostic impact of the neurotensin (NTS) and its cognate receptor (NTSR1) known for mediating cellular proliferation, survival, invasiveness, and mobility. We studied a series of 52 consecutive patients with epithelioid malignant mesothelioma undergoing management with curative intent, by immunohistochemistry for the expression of NTS and NTSR1. Specimens were scored as 0, 1, or 2 for less than 10%, between 10 and 50%, or more than 50% of NTS positive staining in tumor cells, respectively. Immunohistochemistry revealed that NTS and NTSR1 expression was found in 71.1% and 90.4% of malignant mesotheliomas, respectively. Using univariate analysis, expression of NTS was significantly (p = 0.015) related with a poor prognosis, with median survivals of 11.0 months, 18.4 months, and 29.8 months in patients showing expression scored as 2, 1, and 0, respectively. Multivariate analysis showed that expression of NTS (p = 0.007) and non-surgical therapy (p = 0.004) were independent predictors of poor prognosis. In order to evaluate the role of NTS/NTSR1 complex in mesothelioma progression, in vitro cell invasion assays and wound healing were performed on the mesothelioma cell line, MSTO-211H, and showed that inhibition of the NTS system resulted in a significant reduction of both migration and collagen invasion of mesothelioma cells. The expression of NTS is identified as a prognostic marker in patients with malignant pleural mesothelioma (Patent EP 08305971.7)., (2009 Elsevier Masson SAS. All rights reserved.)

Background: The neurotensin (NTS) and its specific high affinity G protein coupled receptor, the NT1 receptor (NTSR1), are considered to be a good candidate for one of the factors implicated in neoplastic progression. In breast cancer cells, functionally expressed NT1 receptor coordinates a series of transforming functions including cellular migration and invasion., Methods and Results: we investigated the expression of NTS and NTSR1 in normal human breast tissue and in invasive ductal breast carcinomas (IDCs) by immunohistochemistry and RT-PCR. NTS is expressed and up-regulated by estrogen in normal epithelial breast cells. NTS is also found expressed in the ductal and invasive components of IDCs. The high expression of NTSR1 is associated with the SBR grade, the size of the tumor, and the number of metastatic lymph nodes. Furthermore, the NTSR1 high expression is an independent factor of prognosis associated with the death of patients., Conclusion: these data support the activation of neurotensinergic deleterious pathways in breast cancer progression.

Helicobacter pylori is unique because of the unusually high number and diversity of its restriction modification (R-M) systems. HpyC1I R-M was recently characterized and contains an endonuclease which is an isoschizomer of the endonuclease BccI. This R-M is involved in adherence to gastric epithelial cells, a crucial step in bacterial pathogenesis. This observation illustrates the fact that R-M systems have other putative biological functions in addition to protecting the bacterial genome from external DNA. The genomic diversity of HpyC1I R-M was evaluated more precisely on a large collection of H. pylori strains by PCR, susceptibility to BccI digestion and sequencing. The results obtained support the mechanism of gain and loss of this R-M system in the H. pylori genome, and suggest that it is an ancestral system which gradually disappears during H. pylori evolution, following successive steps: (1) inactivation of the endonuclease gene, followed or accompanied by: (2) inactivation of the methyltransferase genes, and then: (3) definitive loss, leaving only short endonuclease remnant sequences.

Emerging evidence supports neurotensin as a trophic and antiapoptotic factor, mediating its control via the high-affinity neurotensin receptor (NT1 receptor) in several human solid tumors. In a series of 51 patients with invasive ductal breast cancers, 34% of all tumors were positive for neurotensin and 91% positive for NT1 receptor. We found a coexpression of neurotensin and NT1 receptor in a large proportion (30%) of ductal breast tumors, suggesting a contribution of the neurotensinergic signaling cascade within breast cancer progression. Functionally expressed NT1 receptor, in the highly malignant MDA-MB-231 human breast cancer cell line, coordinated a series of transforming functions, including cellular migration, invasion, induction of the matrix metalloproteinase (MMP)-9 transcripts, and MMP-9 gelatinase activity. Disruption of NT1 receptor signaling by silencing RNA or use of a specific NT1 receptor antagonist, SR48692, caused the reversion of these transforming functions and tumor growth of MDA-MB-231 cells xenografted in nude mice. Our findings support the contribution of neurotensin in human breast cancer progression and point out the utility to develop therapeutic molecules targeting neurotensin or NT1 receptor signaling cascade. These strategies would increase the range of therapeutic approaches and be beneficial for specific patients.

Helicobacter pylori has been associated with the development of two malignant diseases: gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Although the cag pathogenicity island, especially the cagA gene, has been linked with adenocarcinoma, few data concerning H. pylori pathogenic factors involved in low-grade gastric MALT lymphoma are available. The goal of this study was to analyze the prevalence of and correlation between genes coding for seven H. pylori virulence factors (cagA, cagE, vacA, iceA, babA, hopQ, and oipA) and two novel adhesins (sabA and hopZ) by comparing a collection of 43 H. pylori strains isolated from patients with low-grade gastric MALT lymphoma to 39 strains isolated from age-matched patients with gastritis only. Our results show that taken individually, none of the nine genes tested can be considered associated with MALT strains and allow us to conclude that MALT pathogenesis is not linked with more proinflammatory H. pylori strains. We demonstrated that in patients infected with strains harboring the iceA1 allele, sabA functional status, and hopZ "off" status, the odds of developing a MALT lymphoma were 10 times higher. However, the low prevalence of such strains (10 of 43 MALT strains) renders this triple association a low-sensitivity marker for MALT strains. Our data confirmed that H. pylori virulence factors are correlated with one another. If the involvement of H. pylori in MALT lymphoma is well established, the pathomechanism by which gastric lymphoma occurs remains to be identified.