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The backbone of induction therapy in acute myeloid leukaemia (AML) is to use an anthracycline in combination with cytarabine. Despite recent advances in AML therapy, this treatment remains the standard, and it has been largely unchanged for decades. There are few curative options for patients unfit for this treatment. The anti-protozoal agent emetine improves efficacy of anthracycline treatment towards AML in vitro and in vivo but the effect is more potent when emetine is administered 30 minutes after anthracyclines. To delay the onset of protein synthesis inhibition we produced a novel inactive emetine prodrug and co-encapsulated this with the anthracycline daunorubicin (DNR) in liposomes. Nanoencapsulation protects the prodrug from degradation in the blood and ensure simultaneous delivery of both drugs to cancer cells. The prodrug concept will delay the onset of action of emetine relative to DNR. In AML cells, the combination of DNR and the emetine-prodrug in liposomes increased cytotoxicity compared to liposomes with DNR and native emetine. Liposomes loaded with the emetine prodrug did not show increased toxicity towards non-cancerous cell lines and zebrafish larvae. In patients, a liposomal formulation such as that presented herein could allow for a reduced DNR dose without compromising efficacy, thereby reducing toxic side effects and enabling improved therapy for patients not fit for current treatment options., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Lars Herfindal reports financial support was provided by Childhood Cancer Association. Edvin Tang Gundersen reports financial support was provided by Western Norway Regional Health Authority. Ingeborg N Reiten reports financial support was provided by Research Council of Norway. Francois-Xavier Legrand reports financial support was provided by National Centre for Scientific Research. David Chapron reports financial support was provided by National Centre for Scientific Research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

A series of 3,5-disubtituted pyridin-2(1 H )-ones was synthesized. As part of a structure-activity relationship study performed in this series, structural modifications were based on 3-(indol-4-yl)-5-(pyridin-4-ylamino)pyridin-2(1 H )-one B, which exhibited a potent anti-allodynic effect in a rat model of inflammatory pain. In this study, new compounds were assessed for their ability to inhibit cutaneous mechanical allodynia in rats by using the capsaicin pain model. Compound 36, a 2-methoxypyridine derivative, yielded the most promising outcome, demonstrating an enhanced analgesic effect., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Novel fluorinated foldamers based on aminomethyl-1,4-triazolyl-difluoroacetic acid (1,4-Tz-CF 2 ) units were synthesized and their conformational behaviour was studied by NMR and molecular dynamics. Their activity on the aggregation of the human islet amyloid polypeptide (hIAPP) amyloid protein was evaluated by fluorescence spectroscopy and mass spectrometry. The fluorine labelling of these foldamers allowed the analysis of their interaction with the target protein. We demonstrated that the preferred extended conformation of homotriazolamers of 1,4-Tz-CF 2 unit increases the aggregation of hIAPP, while the hairpin-like conformation of more flexible heterotriazolamers containing two 1,4-Tz-CF 2 units mixed with natural amino acids from the hIAPP sequence reduces it, and more efficiently than the parent natural peptide. The longer heterotriazolamers having three 1,4-Tz-CF 2 units adopting more folded hairpin-like and ladder-like structures similar to short multi-stranded β-sheets have no effect. This work demonstrates that a good balance between the structuring and flexibility of these foldamers is necessary to allow efficient interaction with the target protein., (© 2024 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Pyrazole analogues of the staurosporine aglycone K252c, in which the lactam ring was replaced by a pyrazole moiety, were synthesized. In this series, one or the other nitrogen atoms of the indolocarbazole scaffold was substituted by aminoalkyl chains, aiming at improving protein kinase inhibition as well as cellular potency toward acute myeloid leukemia (AML) cell lines. Compound 19a, substituted at the N12-position by a 3-(methylamino)propyl group, showed high cellular activity in the low micromolar range toward three AML cell lines (MOLM-13, OCI-AML3 and MV4-11) with selectivity over non-cancerous cells (NRK, H9c2). 19a is also a highly potent inhibitor of the three Pim kinase isoforms, Pim-3 being the most inhibited with an IC 50 value in the nanomolar range. A selectivity screening toward a panel of 50 protein kinases showed that 19a also potently inhibited PRK2 and to a lower extent AMPK, MARK3, GSK3β and JAK3. Our results enhance the understanding of the structural characteristics of indolopyrazolocarbazoles essential for potent protein kinase inhibition with therapeutic potential against AML., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Serine-threonine protein kinases of the DYRK and CLK families regulate a variety of vital cellular functions. In particular, these enzymes phosphorylate proteins involved in pre-mRNA splicing. Targeting splicing with pharmacological DYRK/CLK inhibitors emerged as a promising anticancer strategy. Investigation of the pyrido[3,4- g ]quinazoline scaffold led to the discovery of DYRK/CLK binders with differential potency against individual enzyme isoforms. Exploring the structure-activity relationship within this chemotype, we demonstrated that two structurally close compounds, pyrido[3,4- g ]quinazoline-2,10-diamine 1 and 10-nitro pyrido[3,4- g ]quinazoline-2-amine 2 , differentially inhibited DYRK1-4 and CLK1-3 protein kinases in vitro. Unlike compound 1 , compound 2 efficiently inhibited DYRK3 and CLK4 isoenzymes at nanomolar concentrations. Quantum chemical calculations, docking and molecular dynamic simulations of complexes of 1 and 2 with DYRK3 and CLK4 identified a dramatic difference in electron donor-acceptor properties critical for preferential interaction of 2 with these targets. Subsequent transcriptome and proteome analyses of patient-derived glioblastoma (GBM) neurospheres treated with 2 revealed that this compound impaired CLK4 interactions with spliceosomal proteins, thereby altering RNA splicing. Importantly, 2 affected the genes that perform critical functions for cancer cells including DNA damage response, p53 signaling and transcription. Altogether, these results provide a mechanistic basis for the therapeutic efficacy of 2 previously demonstrated in in vivo GBM models.

A structure-activity relationship study performed on 1H-pyrrolo[3,2-g]isoquinoline scaffold identified new haspin inhibitors with nanomolar potencies and selectivity indices (SI) over 6 (inhibitory potency evaluated against 8 protein kinases). Compound 22 was the most active of the series (haspin IC 50  = 76 nM). Cellular evaluation of 22 confirmed its activity for endogenous haspin in U-2 OS cells and its anti-proliferative activity against various cell lines. In addition, the binding mode of analog 22 in complex with haspin was determined by X-ray crystallography., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Chronic exposure to ultraviolet (UV) irradiation causes immunosuppression, photoaging, and carcinogenesis by induction of a cascade of skin damages. Sunscreens currently on the market are not absorbing UV rays uniformly throughout the full UV range, high sun protection factor (SPF) sunscreens absorb most of UVB rays but are less effective in absorbing the UVA part of the spectrum. In the context, one approach could consist of preserving the skin natural resources and mechanisms, which is the foundation of the ecobiological approach, by combing UV filters and antioxidants to enhance their photoprotective effect., Methods: First, the photoprotection properties of ectoine and mannitol association were characterized by the quantification of glutathione, reactive oxygen species, and double-stranded DNA breaks and by the epidermal Langerhans cells functionality. Second, the protection of squalene oxidation, catalase activity, and trans-urocanic acid (UCA) by the ectoine and mannitol association combined or not with SPF30 UV filters was assessed in vivo via non-invasive skin samplings in 10 subjects on irradiated areas., Results: Using in vitro irradiated skin cell models, we demonstrated that this association significantly preserved intracellular glutathione levels, reduced DNA strand breaks induced by oxidative stress, and maintained Langerhans cell functionality. In vivo this association combined with UV filters presented significantly higher protection of three natural defense systems altered by UV compared to UV filters alone: squalene oxidation, catalase activity, and preservation of trans-UCA., Conclusion: This study demonstrates the ecobiological potential of combining UV filters with biological protection to increase skin photoprotection provided by specific active ingredients with antioxidative and immunosuppressive properties., (© 2023 Naos - Aix en Provence and QIMA Bioalternatives. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Introduction: Obesity is a known risk factor for urinary incontinence (UI). As bariatric surgery can result in significant and sustainable weight loss, many chronic diseases closely linked to obesity have likewise shown improvement after surgical weight loss. We propose that bariatric surgery may significantly improve obesity-related UI symptoms as well as improve quality of life., Methods and Procedures: This is an interim analysis of an ongoing, prospective, single-institution observational study looking at UI in women enrolled in a bariatric surgery program. Participants completed the Pelvic Floor Distress Inventory (PFDI-20), International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI-SF), King's Health Questionnaire (KHQ), and Patient Global Impression of Improvement (PGI-I). Questionnaires were administered upon enrollment, pre-operatively, and at 3, 6, and 12 months post-operatively. Demographic data were collected at each interval and analyzed with descriptive statistics., Results: At analysis, 108 patients had enrolled in the study and 60% had progressed to surgery. We analyzed the following surveys: enrollment (n = 108), pre-operative (n = 43), 3-month (n = 29), 6-month (n = 26), and 1-year (n = 27). Mean BMI decreased from 49.8 to 31.1 at 1-year. All surveys showed significant improvement in UI symptoms over time. Overall, UI symptoms (PDFI-20) are correlated with BMI at time of survey and %TBWL (p = 0.03, p = 0.019). Additionally, perception of symptom improvement with surgery (PGI-I) improved over time (3-month p = 0.0289, 6-month p = 0.0024, 12-month p = 0.0035). Quality of life related to UI symptoms (KHQ) significantly improved after surgery (p = 0.0047 3-month, p = 0.0042 6-month, p = 0.0165 1-year)., Conclusions: Although the relationship is complex and likely depends on many factors, weight loss after bariatric surgery is associated with improvement in UI symptoms and UI-related quality of life. Bariatric surgery can play a role in the long-term treatment of UI in women with obesity that may negate the need for further invasive UI procedures., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Secondary hyperparathyroidism (SHPT) after bariatric surgery has significant adverse implications for bone metabolism, increasing the risk for osteoporosis and fracture. Our aim was to characterize prevalence and identify risk factors for SHPT in bariatric surgery patients., Methods: We performed a single-institution, retrospective chart review of patients who underwent bariatric surgery from June 2017 through December 2021. Demographic and clinical data were collected, including serum parathyroid hormone, calcium, and vitamin D3 at enrollment and 3, 6, and 12-months postoperatively. Chi-square or Fisher's exact tests were used to analyze categorical data and Mann-Whitney U test for continuous data. Multivariable analysis using binomial logistic regression assessed risk factors for SHPT. P-values ≤ 0.05 were considered significant., Results: 350 patients were analyzed. SHPT prevalence at any time point was 72.9%. 65.8% had SHPT at enrollment; 45.9% resolved with intensive vitamin supplementation; and 19.7% had recurrent SHPT. New-onset SHPT occurred in 8.6%. Persistent SHPT was present in 42.4% at 1-year. Baseline SHPT correlated with black race and T2DM. SHPT at any time point correlated with T2DM and higher baseline BMI. 1-year SHPT correlated with RYGB, depression, and longer time in program. SHPT was not correlated with %TBWL at any time point. In patients with SHPT, vitamin D3 deficiency prevalence was significantly higher at baseline (77.0%) compared to all post-bariatric time points (16.7%, 17.3%, and 23.1%; P < 0.0001)., Conclusions: SHPT is highly prevalent in patients with obesity seeking weight loss surgery. 42% had persistent SHPT at 1-year despite appropriate vitamin supplementation. Current vitamin D3 and calcium supplementation protocols may not effectively prevent SHPT in many post-bariatric patients. Low prevalence of concomitant vitamin D3 deficiency with SHPT after bariatric surgery suggests that there may be alternative mechanisms in this population. Further studies are needed to develop effective treatment strategies to mitigate the adverse effects of bariatric surgery on bone metabolism., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Synchronization of audio-tactile stimuli represents a key feature of multisensory interactions. However, information on stimuli synchronization remains scarce, especially with virtual buttons. This work used a click sensation produced with traveling waves and auditory stimulus (a bip-like sound) related to a virtual click for a psychological experiment. Participants accomplish a click gesture and judge if the two stimuli were synchronous or asynchronous. Delay injection was performed on the audio (haptic first) or the click (audio first). In both sessions, one stimulus follows the other with a delay ranging from 0-700 ms. We use weighted and transformed 3-up/1-down staircase procedures to estimate people's sensitivity. We found a threshold of 179 ms and 451 ms for the auditory first and haptic first conditions, respectively. Statistical analysis revealed a significant effect between the two stimuli' order for threshold. Participants' acceptable asynchrony decreased when the delay was on the haptic rather than on the audio. This effect could be due to the natural experience in which the stimuli tend to be first tactile and then sonorous rather than the other way around. Our findings will help designers to create multimodal virtual buttons by managing audio-tactile temporal synchronization.

Purpose: Skincare products are used daily to maintain a healthy skin, although their skin microbiome impact is still poorly known. Preserving the natural resources and mechanisms of the skin ecosystem is essential, and a novel approach based on these premises, called ecobiology, has recently emerged in skincare. We evaluated the impact on the skin microbiome of three types of leave-on face skincare products: a hydrophilic solution, a micellar solution, and an oil-in-water emulsion., Patients and Methods: Samples for microbial profiling were obtained from 20 Caucasian females twenty-four hours and four days following daily application of the skincare products and compared to an untreated area. The bacterial diversity and the abundance of the skin microbiome were analyzed by 16S rRNA gene sequencing using an Illumina MiSeq platform., Results: Our results confirmed the skin microbiome diversity and the prevalence of Cutibacterium spp. and Staphylococcus spp. at sebaceous sites. The bacterial diversity and abundance were not affected by the products, and no dissimilarities versus the control nor between each product were noted at both times., Conclusion: These preliminary results demonstrate for the first time that three types of leave-on face skincare products have no impact on the human skin microbiome and can be considered to be "microbiome friendly"., Competing Interests: Sylvie Callejon, Félix Giraud, Florence Larue, Armonie Buisson, Léa Mateos, Laurence Grare, Aurélie Guyoux, Eric Perrier, Nathalie Ardiet, and Sandra Trompezinski are employees of NAOS Group, France., (© 2023 Callejon et al.)

Texture, a fundamental object attribute, is perceived through multisensory information including touch and auditory cues. Coherent perceptions may rely on shared texture representations across different senses in the brain. To test this hypothesis, we delivered haptic textures coupled with a sound synthesizer to generate real-time textural sounds. Participants completed roughness estimation tasks with haptic, auditory, or bimodal cues in an MRI scanner. Somatosensory, auditory, and visual cortices were all activated during haptic and auditory exploration, challenging the traditional view that primary sensory cortices are sense-specific. Furthermore, audio-tactile integration was found in secondary somatosensory (S2) and primary auditory cortices. Multivariate analyses revealed shared spatial activity patterns in primary motor and somatosensory cortices, for discriminating texture across both modalities. This study indicates that primary areas and S2 have a versatile representation of multisensory textures, which has significant implications for how the brain processes multisensory cues to interact more efficiently with our environment., Competing Interests: The authors declare no competing interests., (© 2023.)

This work explores the asymmetry of quantum steering in a setup using high-dimensional entanglement. We construct entangled states with the following properties: (i) one party (Bob) can never steer the state of the other party (Alice), considering the most general measurements, and (ii) Alice can strongly steer the state of Bob, in the sense of demonstrating genuine high-dimensional steering. In other words, Alice can convince Bob that they share an entangled state of arbitrarily high Schmidt number, while Bob can never convince Alice that the state is even simply entangled. In this sense, one-way steering can become unlimited. A key result for our construction is a condition for the joint measurability of all high-dimensional measurements subjected to the combined effect of noise and loss, which is of independent interest.

Hypothesis: The wettability of carbonate rocks is expected to be affected by the organic components of biominerals which are complex, nanostructured organo-mineral assemblages. Elucidating the nanoscale mechanisms driving the wettability of solid surfaces will enable a better understanding of the role of biominerals in the wetting properties of carbonate rocks to control various geological, environmental and industrial processes., Experiments: Using Atomic Force Microscopy and Spectroscopy (AFM/AFS) we probed the wettability properties of carbonate rocks with different amounts of organic material. The adhesion properties of two types of limestones were determined in liquid environments at different length scales (nm to mm) using functionalized tips with different chemical groups to determine the extent of surface hydrophobic and hydrophilic organo-mineral interactions., Findings: We observed homogeneous hydrophobic areas at length scales below < 5 µm. The origin of this hydrophobicity is linked to the presence of organics, whose amount and spatial distribution depend on the rock composition. Specifically, our results reveal that the biogenic vs non-biogenic origin of the mineral grains is the main rock property controlling the wettability of the solid surface. Overall, our methodology offers a multi-scale approach to unravel the role that organic moieties and biominerals play in controlling the wettability of rock-water interfaces., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This paper presents the development of an electronic system that converts an electrically assisted bicycle into an intelligent health monitoring system, allowing people who are not athletic or who have a history of health issues to progressively start the physical activity by following a medical protocol (e.g., max heart rate and power output, training time). The developed system aims to monitor the health state of the rider, analyze data in real-time, and provide electric assistance, thus diminishing muscular exertion. Furthermore, such a system can recover the same physiological data used in medical centers and program it into the e-bike to track the patient's health. System validation is conducted by replicating a standard medical protocol used in physiotherapy centers and hospitals, typically conducted in indoor conditions. However, the presented work differentiates itself by implementing this protocol in outdoor environments, which is impossible with the equipment used in medical centers. The experimental results show that the developed electronic prototypes and the algorithm effectively monitored the subject's physiological condition. Moreover, when necessary, the system can change the training load and help the subject remain in their prescribed cardiac zone. This system allows whoever needs to follow a rehabilitation program to do so not only in their physician's office, but whenever they want, including while commuting.

We synthesized new analogues of the anti-AML agent VS-II-173. We studied the effect of the substitution at the 1- and 5-positions of the pyrazolo[4,3-a]phenanthridine scaffold on Pim-1 kinase inhibition and cytotoxicity against AML MOLM-13 cells. We found that compounds 20 and 21, substituted at the 1-position exhibited stronger Pim-1 inhibition together with a high potency toward MOLM-13 cells, associated with apoptosis induction and selectivity over non-cancerous NRK cells., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Glioblastoma (GBM) is characterized by exceptionally high intratumoral heterogeneity. However, the molecular mechanisms underlying the origin of different GBM cell populations remain unclear. Here, we found that the compositions of ribosomes of GBM cells in the tumour core and edge differ due to alternative RNA splicing. The acidic pH in the core switches before messenger RNA splicing of the ribosomal gene RPL22L1 towards the RPL22L1b isoform. This allows cells to survive acidosis, increases stemness and correlates with worse patient outcome. Mechanistically, RPL22L1b promotes RNA splicing by interacting with lncMALAT1 in the nucleus and inducing its degradation. Contrarily, in the tumour edge region, RPL22L1a interacts with ribosomes in the cytoplasm and upregulates the translation of multiple messenger RNAs including TP53. We found that the RPL22L1 isoform switch is regulated by SRSF4 and identified a compound that inhibits this process and decreases tumour growth. These findings demonstrate how distinct GBM cell populations arise during tumour growth. Targeting this mechanism may decrease GBM heterogeneity and facilitate therapy., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

A new series of pyrazolo[3,4- g ]isoquinoline derivatives, diversely substituted at the 4- or 8-position, were synthesized. The results of the kinase inhibitory potency study demonstrated that the introduction of a bromine atom at the 8-position was detrimental to Haspin inhibition, while the introduction of an alkyl group at the 4-position led to a modification of the kinase inhibition profiles. Altogether, the results obtained demonstrated that new pyrazolo[3,4- g ]isoquinolines represent a novel family of kinase inhibitors with various selectivity profiles.

Background: The optimal treatment duration of ICIs for patients with advanced NSCLC remains uncertain. In phase 3 clinical trials, treatment continued for 2 years or until disease progression with similar long-term survival rates. Real-life data are missing., Patients and Methods: This academic multicentric retrospective study aims at analyzing the characteristics of patients who discontinued treatment after at least 18 months of ICI monotherapy, in the setting of controlled disease., Results: Of the 1127 patients treated with immunotherapy in the given period in six centers, 107 patients had their tumor controlled after at least 18 months of treatment and 54 (50%) of them had discontinued ICI. The median duration of treatment was 26 months. Treatment was stopped due to prescriber choice or toxicity in 46% and 22% of cases, respectively. After a median follow-up of 21 months from ICI discontinuation (95% CI 15.0-26.1 months), 18 (33%) patients experienced tumor progression after a median time of 10.0 months (range 2-33). From discontinuation, 12-month overall survival (OS) and progression-free survival (PFS) were 90% (95% CI 77.7-95.7) and 71% (95% CI 56.8-81.5), respectively; 24-month OS and PFS were 84% (95% CI 68.7-92.2) and 63% (95% CI 46.1-76.2), respectively. Duration of disease control after ICI discontinuation was correlated with tumor response at treatment discontinuation: PFS rate at 12 months was 76% after complete response (CR n = 11) or partial response (PR n = 37) and 22% after only stable disease (SD n = 6) as best response, p-value = 0.0002. PFS rate at 12 months was 80% for CR and/or complete metabolic response with 18F-FDG PET/CT (CMR) and 65% for others. Fourteen patients out of the 18 relapse patients received a subsequent treatment: seven with ICI rechallenge (best response 14% PR and 86% SD) and five with localized therapy with 60% CR., Conclusions: This real-life study provides new insight into long-term outcomes of patients with advanced NSCLC treated with ICI for at least 18 months before treatment discontinuation in the absence of PD. Tumor response and CMR with FDG PET just before therapy discontinuation may be a predictive factor of prolonged disease control upon discontinuation. These results call for caution in discontinuing treatment in patients with stable disease as the best response., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Haspin (haploid germ cell-specific nuclear protein kinase) offers a potential target for the development of new anticancer drugs. Thus, the identification of new inhibitors targeting this protein kinase is of high interest. However, Haspin inhibitors developed to date show a poor selectivity profile over other protein kinases of the human kinome. Here, we identified a new pyridoquinazoline based inhibitor (4), with excellent inhibitory activity and selectivity for Haspin (IC 50 of 50 nM). We describe the structure-activity relationship study including the evaluation of this inhibitor on a large panel of 486 kinases as well as on immortalized or cancer cell lines. In addition, we determined the binding mode of analog 2a in complex with Haspin using X-ray crystallography., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Cell membranes represent a complex and variable medium in time and space of lipids and proteins. Their physico-chemical properties are determined by lipid components which can in turn influence the biological function of membranes. Here, we used hydrostatic pressure to study the close dynamic relationships between lipids and membrane proteins. Experiments on the β-barrel OmpX and the α-helical BLT2 G Protein-Coupled Receptor in nanodiscs of different lipid compositions reveal conformational landscapes intimately linked to pressure and lipids. Pressure can modify the conformational landscape of the membrane protein per se, but also increases the gelation of lipids, both being monitored simultaneously at high atomic resolution by NMR. Our study also clearly shows that a membrane protein can modulate, at least locally, the fluidity of the bilayer. The strategy proposed herein opens new perspectives to scrutinize the dynamic interplay between membrane proteins and their surrounding lipids., (© 2022. The Author(s).)

Friction reduction using ultrasonic longitudinal surface vibration can modify the user perception of the touched surface and induce the perception of textured materials. In the current paper, the mechanisms of friction reduction using longitudinal vibration are analyzed at different finger exploration velocities and directions over a plate. The development of a non-Coulombic adhesion theory based on experimental results is evaluated as a possible explanation for friction reduction with vibrations that are non-collinear with the finger displacement. Comparison with experimental data shows that the model adequately describes the reduction in friction, although it is less accurate for low finger velocities and depends on motion direction.

Mechanical allodynia, a painful sensation caused by innocuous touch, is a major chronic pain symptom, which often remains without an effective treatment. There is thus a need for new anti-allodynic treatments based on new drug classes. We recently synthetized new 3,5-disubstituted pyridin-2(1H)-one derivatives. By substituting the pyridinone at the 3-position by various aryl/heteroaryl moieties and at the 5-position by a phenylamino group, we discovered that some derivatives exhibited a strong anti-allodynic potency in rats. Here, we report that varying the substitution of the pyridinone 5-position, the 3-position being substituted by an indol-4-yl moiety, further improves such anti-allodynic potency. Compared with 2, one of the two most active compounds of the first series, eleven out of nineteen newly synthetized compounds showed higher anti-allodynic potency, with two of them completely preventing mechanical allodynia. In the first series, hit compounds 1 and 2 appeared to be inhibitors of p38α MAPK, a protein kinase known to underlie pain hypersensitivity in animal models. Depending on the substitution at the 5-position, some newly synthetized compounds were also stronger p38α MAPK inhibitors. Surprisingly, though, anti-allodynic effects and p38α MAPK inhibitory potencies were not correlated, suggesting that other biological target(s) is/are involved in the analgesic activity in this series. Altogether, these results confirm that 3,5-disubstituted pyridine-2(1H)-one derivatives are of high interest for the development of new treatment of mechanical allodynia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Immune checkpoint inhibitors (ICI) are dramatically active in a minority of non-small cell lung cancer (NSCLC) patients. We studied here the relationship between patients's metabolism and outcome under ICI., Methods: Metastatic NSCLC patients underwent a nutritional assessment prior to initiating immunotherapy. Resting energy expenditure (REE) was measured (mREE) using ambulatory indirect calorimetry and compared with the theoretical value (tREE) provided by the Harris and Benedict formula. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and disease control rate (DCR) based on investigator review per RECIST v1.1. and overall survival (OS). The association of patient's metabolism with 6-month PFS was first explored in a single-center training cohort to estimate the effect size. The relationship between patient's metabolism and 6-month PFS was then tested in an independent non interventional observational prospective cohort (ELY) of 100 patients recruited in two tertiary university centers., Findings: In the entire cohort, the ORR was 14% for the hypermetabolic group (n = 10/74) vs 38% for the normometabolic group (n = 26/68), respectively (estimated difference 25%, 95CI 9-40%, p = 0.001). The DCR was 28% for the hypermetabolic group (n = 21/74) vs 53% for the normometabolic group (n = 36/68), respectively (estimated difference 25%, 95CI 7-42%, p = 0.005). In the validation cohort (100 patients, 2 centers), normometabolic patients (defined as mREE/tREE < 110%) had increased 6-month PFS (57% versus 22%; odds ratio: 4.76; IC95 [1.87 - 12.89]; p<0.001) and improved overall survival (HR 2.20; IC95: 1.41-3.44; p<0.001). The positive and negative predictive values of normometabolism to identify non-progressive patients at 6 months, were 57% and 78% respectively, sensitivity was 72% and specificity was 66%. In multivariate analysis including PD-L1 tumor status, basal metabolism was an independent predictive factor for 6-month PFS., Interpretation: Normometabolism is a new independent parameter to identify mNSCLC patients who will benefit from ICI, with both improved tumor response, 6-month PFS, and survival., Funding: This work was supported by Baxter (04012016)., Competing Interests: Declaration of Competing Interest Dr. Boudou-Rouquette reports grants from BAXTER, during the conduct of the study; personal fees from Takeda, personal fees from Pharmamar, outside the submitted work. Pr. Goldwasser reports grants and personal fees from BAXTER, personal fees from FRESENIUS KABI, personal fees from NUTRICIA, outside the submitted work. Pr. WISLEZ reports personal fees from Boeringher Ingelheim, personal fees and non-financial support from ROCHE, personal fees and non-financial support from MSD, personal fees from BMS, personal fees from Astra Zeneca, personal fees from Amgen, personal fees from Janssen, outside the submitted work. Dr. Fabre reports grants from BMS, board membership from ROCHE, Astra Zeneca, and payment for development of educational presentations, from Astra Zeneca, outside the submitted work. Dr. Alexandre reports grants and personal fees from MSD, personal fees from ASTRA ZENECA, personal fees from EISAI, grants and non-financial support from JANSSEN, personal fees and non-financial support from GSK, outside the submitted work. Dr. Arrondeau, Dr. Gervais, Dr. Lupo, Dr. Villeminey, Dr. Piketty, Dr. Durand, Dr Giraud, Dr. Jouinot, Dr. Ulmann, Dr. De Percin, Pr Damotte and Pr. Alifano have nothing to disclose., (Copyright © 2021. Published by Elsevier B.V.)

When a finger touches an ultrasonic vibrating plate, a non-sinusoidal contact force is produced. This force is called acoustic finger force. In a setup where closed-loop control is performed on the vibration amplitude, a component of the acoustic finger force can be measured at the fundamental vibration frequency of the plate. This calculation is obtained from the measurement of the variation of the controller voltage between the no-load case and when a finger is present. This calculation is made for a group of twelve participants. From these results a PCA (Principal Component Analysis) model is created. This model permits estimation of the acoustic finger force response of a participant at any vibration amplitude, based on a one or two point measurement. Finally, a linear relation between the PCA coefficients and the friction reduction is proposed. The objective of this relation would be to ultimately provide the means to create an amplitude reference calibration based on the desired friction reduction level, and thus be able to produce a standardized tactile feedback for each user, despite the biomechanical differences in finger pad properties between subjects.

The purpose of this review is to underline the protein kinases that have been established, either in fundamental approach or clinical trials, as potential biological targets in pain management. Protein kinases are presented according to their group in the human kinome: TK (Trk, RET, EGFR, JAK, VEGFR, SFK, BCR-Abl), CMGC (p38 MAPK, MEK, ERK, JNK, ASK1, CDK, CLK2, DYRK1A, GSK3, CK2), AGC (PKA, PKB, PKC, PKMζ, PKG, ROCK), CAMK, CK1 and atypical/other protein kinases (IKK, mTOR). Examples of small molecule inhibitors of these biological targets, demonstrating an analgesic effect, are described. Altogether, this review demonstrates the fundamental role that protein kinase inhibitors could play in the development of new pain treatments.

Combining multisensory sources is crucial to interact with our environment, especially for older people who are facing sensory declines. Here, we examined the influence of textured sounds on haptic exploration of artificial textures in healthy younger and older adults by combining a tactile device (ultrasonic display) with synthetized textured sounds. Participants had to discriminate simulated textures with their right index while they were distracted by three disturbing, more or less textured sounds. These sounds were presented as a real-time auditory feedback based on finger movement sonification and thus gave the sensation that the sounds were produced by the haptic exploration. Finger movement velocity increased across both groups in presence of textured sounds (Rubbing or Squeaking) compared to a non-textured (Neutral) sound. While young adults had the same discrimination threshold, regardless of the sound added, the older adults were more disturbed by the presence of the textured sounds with respect to the Neutral sound. Overall, these findings suggest that irrelevant auditory information was taken into account by all participants, but was appropriately segregated from tactile information by young adults. Older adults failed to segregate auditory information, supporting the hypothesis of general facilitation of multisensory integration with aging.

The Ministère de l'Enseignement Supérieur et de la Recherche (MESR) is thanked for financial support for José Laxio Arenas. The China Scholarship Council is thanked for financial support for Yaochun Xu. The authors thank Pr. Vadim Soloshonok and TOSOH F-TECH, Inc. for the kind gift of N-terbutyl-sulfinylimine., (© 2021 Wiley-VCH GmbH.)

In this article, we review the current technology underlying surface haptics that converts passive touch surfaces to active ones (machine haptics), our perception of tactile stimuli displayed through active touch surfaces (human haptics), their potential applications (human-machine interaction), and finally, the challenges ahead of us in making them available through commercial systems. This article primarily covers the tactile interactions of human fingers or hands with surface-haptics displays by focusing on the three most popular actuation methods: vibrotactile, electrostatic, and ultrasonic.

Plant defense stimulators, used in crop protection, are an attractive option to reduce the use of conventional crop protection products and optimize biocontrol strategies. These products are able to activate plant defenses and thus limit infection by pathogens. However, the effectiveness of these plant defense stimulators remains erratic and is potentially dependent on many agronomic and environmental parameters still unknown or poorly controlled. The developmental stage of the plant as well as its fertilization, and essentially nitrogen nutrition, play major roles in defense establishment in the presence of pathogens or plant defense stimulators. The major nitrogen source used by plants is nitrate. In this study, we investigated the impact of Arabidopsis thaliana plant developmental stage and nitrate nutrition on its capacity to mount immune reactions in response to two plant defense stimulators triggering two major defense pathways, the salicylic acid and the jasmonic acid pathways. We show that optimal nitrate nutrition is needed for effective defense activation and protection against the pathogenic bacteria Dickeya dadantii and Pseudomonas syringae pv. tomato . Using an npr1 defense signaling mutant, we showed that nitrate dependent protection against D. dadantii requires a functional NPR1 gene. Our results indicate that the efficacy of plant defense stimulators is strongly affected by nitrate nutrition and the developmental stage. The nitrate dependent efficacy of plant defense stimulators is not only due to a metabolic effect but also invloves NPR1 mediated defense signaling. Plant defense stimulators may have opposite effects on plant resistance to a pathogen. Together, our results indicate that agronomic use of plant defense stimulators must be optimized according to nitrate fertilization and developmental stage., (Copyright © 2020 Verly, Djoman, Rigault, Giraud, Rajjou, Saint-Macary and Dellagi.)

New Delhi metallo-β-lactamase-1 (NDM-1) has recently emerged as a global threat because of its ability to confer resistance to all common β-lactam antibiotics. Understanding the molecular basis of β-lactam hydrolysis by NDM is crucial for designing NDM inhibitors or β-lactams resistant to their hydrolysis. In this study, for the first time, NMR was used to study the influence of Zn(II) ions on the dynamic behavior of NDM-1. Our results highlighted that the binding of Zn(II) in the NDM-1 active site induced several structural and dynamic changes on active site loop 2 (ASL2) and L9 loops and on helix α2. We subsequently studied the interaction of several flavonols: morin, quercetin, and myricetin were identified as natural and specific inhibitors of NDM-1. Quercetin conjugates were also synthesized in an attempt to increase the solubility and bioavailability. Our NMR investigations on NDM-1/flavonol interactions highlighted that both Zn(II) ions and the residues of the NDM-1 ASL1, ASL2, and ASL4 loops are involved in the binding of flavonols. This is the first NMR interaction study of NDM-1/inhibitors, and the models generated using HADDOCK will be useful for the rational design of more active inhibitors, directed against NDM-1., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Introduction: Since 2011, the French government estimates that about 500 French children have been born in or taken by their parents to areas where terrorist operations prevail. Since May 2017, 75 children who returned to France have benefited from a dedicated health care system., Method: This article is the result of clinical interviews conducted with 53 patients evaluated and taken care of at Avicenne Hospital in Bobigny. To our knowledge, no studies have been published on this subject., Results: A total of 32 evaluations have been completed, all of which indicated the need for care for these children. Of these children, 64% are under 5 years old, and 59% were born in France. Their clinical profiles are heterogeneous and fluctuate with time., Discussion: The multiple adverse events experienced by these children and the uniqueness of children born to families suspected by authorities of having participated in activities related to terrorism make this situation unprecedented. How can we make a diagnosis of PTSD without the help of a precise anamnesis? How can we help these children form a structuring narrative that avoids the pitfalls inherent to generalized fascination?, (Copyright © 2020 Klein, Mapelli, Veyret-Morau, Levy-Bencheton, Giraud, di Chiara, Fumagalli, Lida-Pulik, Moscoso, Payen de la Garanderie, Palazzi, Baleyte, Speranza, Rezzoug and Baubet.)

Mechanical Allodynia (MA), a frequent chronic pain symptom caused by innocuous stimuli, constitutes an unmet medical need, as treatments using analgesics available today are not always effective and can be associated with important side-effects. A series of 3,5-disubstituted pyridin-2(1H)-ones was designed, synthesized and evaluated in vivo toward a rat model of inflammatory MA. We found that the series rapidly and strongly prevented the development of MA. 3-(2-Bromophenyl)-5-(phenylamino)pyridin-2(1H)-one 69, the most active compound of the series, was also able to quickly reverse neuropathic MA in rats. Next, when 69 was evaluated toward a panel of 50 protein kinases (PK) in order to identify its potential biological target(s), we found that 69 is a p38α MAPK inhibitor, a PK known to contribute to pain hypersensitivity in animal models. 3,5-Disubstituted pyridin-2(1H)-ones thus could represent a novel class of analgesic for the treatment of MA., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool for reaction monitoring. Several devices have been recently developed for online monitoring, using flow NMR, of batch reactions carried out under realistic experimental conditions in terms of, e.g., agitation and temperature. Here we show that time series of single-scan ultrafast 2D NMR (UF2DNMR) spectra can be collected to monitor solution mixtures that circulate in a flow unit. Fast multidimensional NMR methods have the demonstrated potential to provide kinetic and mechanistic information on reactions. UF2DNMR makes it possible to collect 2D data sets in less than one second, but relies on spatial encoding (SPEN) that is sensitive to sample motion, thus making online monitoring challenging. We characterize the interference between flow and spatial encoding and provide pulse-sequence- and hardware-based solutions. The resulting method is illustrated with the monitoring of a saponification reaction. UF2DNMR with a flow unit is a promising tool for the online monitoring of organic chemical reactions.

In nature, climbing trees and pipes of varying diameters or even navigating inside of hollow pipes and tree holes is easy for some climbing animals and insects. However, today's pipe-climbing robots, which are important for automatically conducting periodic inspections and maintenance of pipelines to save time and keep humans away from hazardous environments, are designed mainly for a specific task, limiting their adaptability to different working scenarios and further implementation in real-life. In this paper, we propose a pipe-climbing robot with a soft linear actuator for bioinspired propulsion, two origami clutches to realize multi-degrees-of-freedom (DoF) motion and two pairs of soft modular legs for multimodal climbing. Design, modeling and experimental validation of the origami clutch are introduced in detail. Preliminary experimental results show that we can achieve a stroke of up to 289.6% and a maximum 45° bending angle on the soft linear actuator by regulating the air pressure inside the soft actuator and origami clutches. Additionally, by choosing the leg-type, three climbing modes, including out-pipe versatile mode, out-pipe high-force mode and in-pipe mode can be realized for particular working scenarios. A prototype climbing robot demonstrates that in out-pipe versatile mode, the robot can climb on the exterior of pipes made of various materials including PVC, rubber and metal with diameters ranging from 105 to 117 mm. In the out-pipe high-force mode, the climber can navigate along a specific pipe carrying maximum 675 g external load at the top or 200 g hanging from the bottom, as well as keeping functional without failure under static loads as high as 1968 g. In the in-pipe mode, the robot is able to travel inside pipes. This research might bridge the design gap between in-pipe and out-pipe climbing robots while offering an alternative option for soft robots to execute multi-DoF motion.

Background: The occurrence of severe, acute limiting toxicity in patients receiving anti-programmed cell death receptor-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found to be associated with anti-cytotoxic T-lymphocyte-associated protein 4 acute toxicity. We explore the clinical and pharmacological parameters influencing nivolumab toxicity, including body composition., Methods: From June 2015 to January 2017, all consecutive patients treated with nivolumab in our institution were prospectively included. We studied the relationship between muscle mass assessed by computed tomography, nivolumab trough level (C min ) at day 14 assessed using the enzyme-linked immunosorbent assay method, and the occurrence of immune grade III or IV toxicity or any toxicity leading to treatment discontinuation (immune-related acute limiting toxicity [irALT])., Results: In our population (n = 92) with a majority of lung cancer (72%), forty-five (51.7%) patients were sarcopenic. The median plasma nivolumab C min at day 14 was 15.4 μg/mL (interquartile range = 11.8-21.0). In multivariate analysis, hypoalbuminaemia (<35 g/L) was independently associated with low nivolumab C min on day 14 (odds ratio [OR] = 0.09; 95% confidence interval [CI] = 0.01-0.59, p = 0.01) and overweight/obesity with high nivolumab C min on day 14 (OR = 5.94; 95% CI = 1.25-28.29, p = 0.03). We observed 22 irALTs in 19 patients (21%). The most frequent irALT was respiratory (6.5%) disorders and gastrointestinal (4.3%) disorders. Patients with sarcopenia were at significantly increased risk of experiencing an irALT (OR = 3.84; 95% CI = 1.02-14.46, p = 0.047). No association was found between toxicity and nivolumab plasma C min at day 14., Conclusions: Our results highlight the importance of assessing body composition and suggest that sarcopenia could predict severe immune-related toxicity of nivolumab in real life., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Pharmacokinetic/pharmacodynamic data from real-world cohort are sparse in non small-cell lung cancer (NSCLC) patients treated with nivolumab. The aim of this prospective observational study was to explore the exposure-response relationship for effectiveness and toxicity of nivolumab in 81 outpatients with metastatic lung cancer. Nivolumab plasma trough concentrations (Cmin) were assayed at days 14, 28, and 42. Prognostic factors (including Cmin) regarding progression-free survival (PFS) and overall survival (OS) were explored using a multivariate Cox model. A Spearman's rank test was used to investigate the relationship between Cmin and grade >2 immune-related adverse events (irAE). Mean nivolumab Cmin was 16.2 ± 6.0 µg/mL ( n = 76), 25.6 ± 10.2 µg/mL ( n = 64) and 33.4 ± 11.3 µg/mL ( n = 53) at days 14, 28, and 42, respectively. No pharmacokinetic/pharmacodynamic (PK/PD) relationship was observed with either survival or onset of irAE. Multivariable Cox regression analysis identified Eastern Cooperative Oncology Group Performance Status (hazard ratio 1.85, 95%confidence interval 1.02-3.38, p -value = 0.043) and baseline use of corticosteroids (HR 8.08, 95%CI 1.78-36.62, p -value = 0.007) as independent risk factor for PFS and only baseline use of corticosteroids (HR 6.29, 95%CI 1.46-27.08, p -value = 0.013) for OS. No PK/PD relationship for nivolumab was observed in real-world NSCLC patients. This supports the recent use of flat dose regimens without plasma drug monitoring.

Background: Many nuclear medicine departments have equipped themselves with automated dispensing systems (ADS) for PET radiopharmaceuticals, in both the operators' and the patients' interests. Whether partially or fully automated, to date there is no marketed ADS representing a true "closed-system". Despite the sterile, injectable nature of ready-to-use radiopharmaceutical drug solutions manipulated by these systems, neither manufacturer's recommendation nor literature report was found about specific qualification of the process' sterility, or about operators' qualification on these dispensing systems. We set up a master plan validation in a radiopharmacy equipped with Trasis Unidose®, including: 1) monthly process-simulating media-fill tests and microbiological contamination assessments of the ADS surfaces; 2) initial and periodic qualification of the operators. The microbiological qualification consisted in surface biocontamination assessment on critical zones with Tryptic-Soy agar. The operator qualification consisted in the evaluation of the operators' knowledge and skills for using the ADS., Results: This study highlighted a minor, handborne microbiological contamination on our first assessment, that corrective actions solved. We therefore decided to brief our operators once a month on microbiological control results, hygiene and good practices, with the support of the present case illustrating the biodecontamination efficiency., Conclusions: As the automation of PET monodose conditioning process still implies human intervention for material preparation and manual biodecontamination, this study illustrates that initial and periodic qualification of the environment and the conditioning process of ADS, including microbiological qualification and operators' qualification, are needed to meet specifications.

New pyrido[3,4-g]quinazoline derivatives were prepared and evaluated for their inhibitory potency toward 5 protein kinases (CLK1, DYRK1A, GSK3, CDK5, CK1). A related pyrido[4,3-h]quinazoline scaffold with an angular structure was also synthesized and its potency against the same protein kinase panel was compared to the analogous pyrido[3,4-g]quinazoline. Best results were obtained for 10-nitropyrido[3,4-g]quinazoline 4 toward CLK1 with nanomolar activities., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Genoidentical HSCT is currently the only curative treatment for SCA, preventing further vascular complications in high-risk children. Studies on the psychological implications of HSCT for recipient, sibling donor, and the rest of the family have been limited in SCA. This study enrolled ten families and used semi-structured interviews to explore the parents' experience at three time points: first before transplantation, then 3 months later, and 1 year later. Three themes emerged from the results: (a) the presence of anxiety, experienced throughout the process, and alleviated by coping strategies (positive thinking, family support, praying); (b) the ability to remain parents to recipient and other family members, despite apprehension and feelings of helplessness, reinforced by the mobilization of important resources at the individual/family levels; (c) the ability to acknowledge the opportunity for their child to be cured of the disease, despite feelings of guilt toward families without a donor, or their own families back home. Overall, the parental experience with HSCT is complex, involving intra-psychic, familial, cultural, religious, and existential factors. Thus, it is important for medical teams to be cognizant of these issues in order to provide the best support to families during the HSCT process., (2019 Wiley Periodicals, Inc.)

Cdc2-like kinase 1 (CLK1) and dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) are involved in the regulation of alternative pre-mRNA splicing. Dysregulation of this process has been linked to cancer progression and neurodegenerative diseases, making CLK1 and DYRK1A important therapeutic targets. Here we describe the synthesis of new pyrido[3,4-g]quinazoline derivatives and the evaluation of the inhibitory potencies of these compounds toward CDK5, CK1, GSK3, CLK1 and DYRK1A. Introduction of aminoalkylamino groups at the 2-position resulted in several compounds with low nanomolar affinity and selective inhibition of CLK1 and/or DYRK1A. Their evaluation on several immortalized or cancerous cell lines showed varying degree of cell viability reduction. Co-crystal structures of CLK1 with two of the most potent compounds revealed two alternative binding modes of the pyrido[3,4-g]quinazoline scaffold that can be exploited for future inhibitor design., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

More than 40 years ago, the present standard induction therapy for acute myeloid leukemia (AML) was developed. This consists of the metabolic inhibitor cytarabine (AraC) and the cytostatic topoisomerase 2 inhibitor daunorubucin (DNR). In light of the high chance for relapse, as well as the large heterogeneity, novel therapies are needed to improve patient outcome. We have tested the anti-AML activity of 15 novel compounds based on the scaffolds pyrrolo[2,3- a ]carbazole-3-carbaldehyde, pyrazolo[3,4- c ]carbazole, pyrazolo[4,3- a ]phenanthridine, or pyrrolo[2,3- g ]indazole. The compounds were inhibitors of Pim kinases, but could also have inhibitory activity against other protein kinases. Ser/Thr kinases like the Pim kinases have been identified as potential drug targets for AML therapy. The compound VS-II-173 induced AML cell death with EC 50 below 5 μmol/L, and was 10 times less potent against nonmalignant cells. It perturbed Pim-kinase-mediated AML cell signaling, such as attenuation of Stat5 or MDM2 phosphorylation, and synergized with DNR to induce AML cell death. VS-II-173 induced cell death also in patients with AML blasts, including blast carrying high-risk FLT3-ITD mutations. Mutation of nucleophosmin-1 was associated with good response to VS-II-173. In conclusion new scaffolds for potential AML drugs have been explored. The selective activity toward patient AML blasts and AML cell lines of the pyrazolo-analogue VS-II-173 make it a promising drug candidate to be further tested in preclinical animal models for AML., (©2019 American Association for Cancer Research.)

The anti-tumour and anti-metastatic properties of heparins have not been tested in patients with early stage cancer. Whether adjuvant low molecular weight heparin (LMWH) tinzaparin impacts the survival of patients with resected non-small cell lung cancer (NSCLC) was investigated.Patients with completely resected stage I, II or IIIA NSCLC were randomly allocated to receive subcutaneous tinzaparin 100 IU·kg -1 once a day for 12 weeks or no treatment in addition to standard of care. The trial was open-label with blinded central adjudication of study outcomes. The primary outcome was overall survival.In 549 patients randomised to tinzaparin (n=269) or control (n=280), mean±sd age was 61.6±8.9 years, 190 (34.6%) patients had stage II-III disease, and 220 (40.1%) patients received adjuvant chemotherapy. Median follow-up was 5.7 years. There was no significant difference in overall survival between groups (hazard ratio (HR) 1.24, 95% CI 0.92-1.68; p=0.17). There was no difference in the cumulative incidence of recurrence between groups (subdistribution HR 0.94, 95% CI 0.68-1.30; p=0.70).Adjuvant tinzaparin had no detectable impact on overall and recurrence-free survival of patients with completely resected stage I-IIIA NSCLC. These results do not support further clinical evaluation of LMWHs as anti-tumour agents., Competing Interests: Conflict of interest: G. Meyer reports grants and non-financial support from Leo Pharma, outside the submitted work. Conflict of interest: B. Besse has nothing to disclose. Conflict of interest: H. Doubre has nothing to disclose. Conflict of interest: A. Charles-Nelson has nothing to disclose. Conflict of interest: S. Aquilanti reports non-financial support from Leo Pharma, outside the submitted work. Conflict of interest: A. Izadifar has nothing to disclose. Conflict of interest: R. Azarian has nothing to disclose. Conflict of interest: I. Monnet has nothing to disclose. Conflict of interest: C. Lamour has nothing to disclose. Conflict of interest: R. Descourt has nothing to disclose. Conflict of interest: G. Oliviero has nothing to disclose. Conflict of interest: L. Taillade has nothing to disclose. Conflict of interest: C. Chouaid has nothing to disclose. Conflict of interest: F. Giraud has nothing to disclose. Conflict of interest: P-E. Falcoz has nothing to disclose. Conflict of interest: M-P. Revel has nothing to disclose. Conflict of interest: V. Westeel has nothing to disclose. Conflict of interest: A. Dixmier has nothing to disclose. Conflict of interest: J. Tredaniel has nothing to disclose. Conflict of interest: S. Dehette has nothing to disclose. Conflict of interest: C. Decroisette has nothing to disclose. Conflict of interest: A. Prevost has nothing to disclose. Conflict of interest: E. Pichon has nothing to disclose. Conflict of interest: E. Fabre has nothing to disclose. Conflict of interest: J-C. Soria has nothing to disclose. Conflict of interest: S. Friard has nothing to disclose. Conflict of interest: J-B. Stern has nothing to disclose. Conflict of interest: L. Jabot has nothing to disclose. Conflict of interest: G. Dennewald has nothing to disclose. Conflict of interest: G. Pavy has nothing to disclose. Conflict of interest: P. Petitpretz has nothing to disclose. Conflict of interest: J-M. Tourani has nothing to disclose. Conflict of interest: M. Alifano has nothing to disclose. Conflict of interest: Dr. Chatellier has nothing to disclose. Conflict of interest: P. Girard reports personal fees and non-financial support from Leo Pharma, outside the submitted work., (Copyright ©ERS 2018.)

Lung cancer is the leading cause of cancer deaths in France, with about 30,000 deaths per year. The overwhelming majority (90 %) are tobacco-related. The prognosis is dark but great therapeutic advances have been made with the development of targeted therapies first and then immunotherapy afterwards. These medications are conditioned to the expression of biomarkers that require specific tools in routine to measure them. We will detail in this chapter several techniques of anatomopathology, cytogenetics and molecular biology necessary for the detection of biomarkers in lung cancers, and their applications in thoracic oncology in 2018., (Copyright © 2018. Published by Elsevier Masson SAS.)

Bronchopleural fistula is an uncommon complication occurring especially following lung resection (pneumonectomy) and associated with high morbidity and mortality rates. The treatment is surgical but some studies reported bronchoscopic treatment. Localization and size of the fistula may indicate different endoscopic procedures. This overview described the different endoscopic procedures and their benefits., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A new method for the quantitative analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) of five tyrosine kinase inhibitors (afatinib, crizotinib, osimertinib, erlotinib and nintedanib) used in the treatment of non-small cell lung cancer (NSCLC) was developed and validated in human plasma. Separation was performed on an Accucore ® C18 (2.1 × 50 mm; 2.6 μm) column using a gradient elution of water acidified with 0.1% (v/v) formic acid (A) and acetonitrile containing 0.1% (v/v) formic acid (B) at a flow rate of 500 μL/min. The analytes were detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer after positive ionization with heated electrospray interface. After addition of three isotopically labeled internal standards, plasma pretreatment consisted in a simple protein precipitation. This method presented satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-assay coefficient of variation from 2.6% to 10.6%), accuracy (from 96.1% to 108.5%), recovery and matrix effects. The lower limit of quantification and the linearity of these five tyrosine kinases inhibitors are suitable with the expected concentrations in clinical practice. This new bioanalytical method can be used in daily clinical practice for therapeutic drug monitoring of these tyrosine kinase inhibitors in NSCLC patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Incidence and severity of invasive group A Streptococcus infections are of increasing concern in France and worldwide. The risk for secondary infection of close contacts is known but rarely described. We report a case of intrafamilial and life-threatening transmission of emm12 group A Streptococcus.

Ultrasonic vibration is employed to modify the friction of a finger pad in way that induces haptic sensations. A combination of intermittent contact and squeeze film levitation has been previously proposed as the most probable mechanism. In this paper, in order to understand the underlying principles that govern friction modulation by intermittent contact, numerical models based on finite element (FE) analysis and also a spring-Coulombic slider are developed. The physical input parameters for the FE model are optimized by measuring the contact phase shift between a finger pad and a vibrating plate. The spring-slider model assists in the interpretation of the FE model and leads to the identification of a dimensionless group that allows the calculated coefficient of friction to be approximately superimposed onto an exponential function of the dimensionless group. Thus, it is possible to rationalize the computed relative reduction in friction being (i) dependent on the vibrational amplitude, frequency, and the intrinsic coefficient of friction of the device, and the reciprocal of the exploration velocity, and (ii) independent of the applied normal force, and the shear and extensional elastic moduli of the finger skin provided that intermittent contact is sufficiently well developed. Experimental validation of the modelling using real and artificial fingertips will be reported in part 2 of this work, which supports the current modelling.

In Variable Friction Tactile Displays, an ultrasonic standing wave can be used to reduce the friction coefficient between a user's finger sliding and a vibrating surface. However, by principle, the effect is limited by a saturation due to the contact mechanics, and very low friction levels require very high vibration amplitudes. Besides, to be effective, the user's finger has to move. We present a device which uses a travelling wave rather than a standing wave. We present a control that allows to realize such a travelling wave in a robust way, and thus can be implemented on various plane surfaces. We show experimentally that the force produced by the travelling wave has two superimposed contributions. The first one is equal to the friction reduction produced by a standing of the same vibration amplitude. The second produces a driving force in the opposite direction of the travelling wave. As a result, the modulation range of the tangential force on the finger can be extended to zero and even negative values. Moreover, the effect is dependant on the relative direction of exploration with regards to the travelling wave, which is perceivable and confirmed by a psycho-physical study.