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BACKGROUND: Trifluridine/tipiracil (FTD/TPI) is approved in third-line treatment of patients with advanced/metastatic gastric and gastroesophageal junction adenocarcinomas (aGA/GEJA). The association of oxaliplatin with FTD/TPI is promising and the combination of FTD/TPI + oxaliplatin + nivolumab has shown a predictable and manageable safety profile. AIMS: The aim is to evaluate the efficacy and safety of FTD/TPI plus oxaliplatin with or without nivolumab in patients, with HER2 negative aGA/GEJA, unfit for triplet chemotherapy (TFOX/mFLOT regimen), in the first-line metastatic setting in comparison with the standard of care FOLFOX with or without nivolumab. METHODS: This study is a prospective randomised, open label, comparative, multicentre, phase II trial designed to include 118 patients. The primary objective is to evaluate the superiority of FTD/TPI plus oxaliplatin with or without nivolumab over FOLFOX regimen with or without nivolumab in terms of PFS in a population of patients non candidate for triplet chemotherapy. Nivolumab will be used for patients whose tumour express PD-L1 with a CPS score ≥5. DISCUSSION: PRODIGE73-UCGI40-LOGICAN study will provide efficacy and safety data on the association of FTD/TPI plus oxaliplatin with or without nivolumab versus FOLFOX regimen with or without nivolumab in first-line palliative setting, in patients with aGA/GEJA (NCT05476796).
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Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Combinación de Medicamentos , Unión Esofagogástrica , Fluorouracilo , Leucovorina , Nivolumab , Pirrolidinas , Neoplasias Gástricas , Timina , Trifluridina , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Unión Esofagogástrica/patología , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Leucovorina/administración & dosificación , Estudios Multicéntricos como Asunto , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino/administración & dosificación , Oxaliplatino/uso terapéutico , Estudios Prospectivos , Pirrolidinas/administración & dosificación , Pirrolidinas/uso terapéutico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Trifluridina/administración & dosificación , Trifluridina/uso terapéutico , Ensayos Clínicos Controlados no Aleatorios como AsuntoRESUMEN
BACKGROUND: The results of the PRODIGE 42/GERICO 12 study showed that short course radiotherapy had a better tolerance profile than radiochemotherapy, with comparable oncological results. We have included Quality of Life analyses and oncogeriatric evaluations in this study. PATIENTS AND METHODS: In all, 101 patients ≥75 years of age with resectable T3-T4 rectal adenocarcinoma less than 12 cm from the anal margin received short course radiotherapy (5X5 Gy in one week) or radiochemotherapy (50 Gy, 2 y/f and capecitabine 800 mg/m2, 5 days/week) with delayed surgery (7 weeks ± 1) in both groups. The Quality of Life analyses (EORTC QLQ C-30 et ELD14) were conducted upon inclusion, pre-operatively, at 3, 6 and 12 months post-op, together with the oncogeriatric evaluations, including an evaluation of the IADL and ADL scores, walking speed, GDS15, MMSE, MNA. RESULTS: We did not highlight any statistical difference for the global EORTC QLQ-C30 score; several factors are statistically in favor of the short course radiotherapy group at 3 months post-op (cognitive functions, fatigue, appetite). In the case of the ELD14 score, the disease burden is perceived as more negative at 3, 6 and 12 months postop in the radiochemotherapy group. The IADL score deteriorated in 44.8 % of the radiochemotherapy group and 14.8 % of the radiotherapy group (p = 0.032); similarly, the GDS15 depression score was better preserved in the short course radiotherapy group (p = 0.05). An analysis of the other scores: ADL, walking speed, MNA, MMSE did not highlight any statistical difference. CONCLUSION: Short course radiotherapy achieves better results in terms of Quality of Life and preservation of autonomy in patients aged ≥75 treated for locally advanced rectal cancer.
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Neoplasias Primarias Secundarias , Neoplasias del Recto , Anciano , Humanos , Calidad de Vida , Evaluación Geriátrica , Terapia Neoadyuvante/efectos adversos , Quimioradioterapia/métodos , Neoplasias del Recto/patología , Neoplasias Primarias Secundarias/etiología , Estadificación de NeoplasiasRESUMEN
Amphitropic proteins and peptides reversibly partition from solution to membrane, a key process that regulates their functions. Experimental approaches classically used to measure protein partitioning into lipid bilayers, such as fluorescence and circular dichroism, are hardly usable when the peptides or proteins do not exhibit significant polarity and/or conformational changes upon membrane binding. Here, we describe binding to lipid vesicles (B2LiVe), a simple, robust, and widely applicable nuclear magnetic resonance (NMR) method to determine the solution-to-membrane partitioning of unlabeled proteins or peptides. B2LiVe relies on previously described proton 1D-NMR fast-pulsing techniques. Membrane partitioning induces a large line broadening, leading to a loss of protein signals; therefore, the decrease of the NMR signal directly measures the fraction of membrane-bound protein. The method uses low polypeptide concentrations and has been validated on several membrane-interacting polypeptides, ranging from 3 to 54 kDa, with membrane vesicles of different sizes and various lipid compositions.
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Membrana Dobles de Lípidos , Péptidos , Péptidos/química , Membrana Dobles de Lípidos/química , Espectroscopía de Resonancia Magnética , Proteínas de la Membrana , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: There is no specific guideline for the treatment of locally advanced rectal cancers in the elderly. Here we compared R0 resection rate and degradation of autonomy based on the instrumental activities of daily living score between neoadjuvant, short course radiotherapy and chemoradiotherapy in this specific population. PATIENTS AND METHODS: Patients ≥75 years with resectable T3-T4 rectal adenocarcinoma within 12 cm of the anal verge or T2 of the very low rectum were randomised between short course radiotherapy (5 × 5 Gy in one week) and chemoradiotherapy (50 Gy, 2 Gy/f, 5 weeks with capecitabine: 800 mg/m2 twice daily, 5 days per week), with delayed surgery 7 ± 1 weeks for the two arms. RESULTS: One hundred and three eligible patients were enrolled between January 2016 and December 2019 when the trial was closed due to poor accrual. The R0 resection rate (first co-primary objective) was 84.3%; confidence interval 95% [73.26-94.18] in the short course group and 88%; confidence interval 95% [77.77-96.60] in the chemoradiotherapy group (non-inferiority p = 0.28). The deterioration of the instrumental activities of daily living score was not different during the pre-operative phase, it was significantly more deteriorated in the chemoradiotherapy group at 3 months post-operative (44.8% versus 14.8%; p = 0.032) but was not different at 12 months post-operative (second co-primary objective). During pre-operative phase, 9.8% of patients in short course group and 22% of patients in chemoradiotherapy group presented a serious adverse event, but we observed no difference during the post-operative phase between the two groups. CONCLUSION: Although the main objectives of the study were not achieved, the short course radiotherapy followed by delayed surgery could represent a preferred treatment option in patients ≥75 years with locally advanced rectal cancer; a new study must be performed to confirm the improvement in overall and specific survival results.
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Neoplasias del Recto , Recto , Humanos , Anciano , Recto/patología , Actividades Cotidianas , Estadificación de Neoplasias , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Capecitabina , Neoplasias del Recto/patología , Terapia Neoadyuvante/efectos adversos , Fluorouracilo , Protocolos de Quimioterapia Combinada Antineoplásica , Resultado del TratamientoRESUMEN
BACKGROUND: Calmodulin (CaM) is an evolutionarily conserved eukaryotic multifunctional protein that functions as the major sensor of intracellular calcium signaling. Its calcium-modulated function regulates the activity of numerous effector proteins involved in a variety of physiological processes in diverse organs, from proliferation and apoptosis, to memory and immune responses. Due to the pleiotropic roles of CaM in normal and pathological cell functions, CaM antagonists are needed for fundamental studies as well as for potential therapeutic applications. Calmidazolium (CDZ) is a potent small molecule antagonist of CaM and one the most widely used inhibitors of CaM in cell biology. Yet, CDZ, as all other CaM antagonists described thus far, also affects additional cellular targets and its lack of selectivity hinders its application for dissecting calcium/CaM signaling. A better understanding of CaM:CDZ interaction is key to design analogs with improved selectivity. Here, we report a molecular characterization of CaM:CDZ complexes using an integrative structural biology approach combining SEC-SAXS, X-ray crystallography, HDX-MS, and NMR. RESULTS: We provide evidence that binding of a single molecule of CDZ induces an open-to-closed conformational reorientation of the two domains of CaM and results in a strong stabilization of its structural elements associated with a reduction of protein dynamics over a large time range. These CDZ-triggered CaM changes mimic those induced by CaM-binding peptides derived from physiological protein targets, despite their distinct chemical natures. CaM residues in close contact with CDZ and involved in the stabilization of the CaM:CDZ complex have been identified. CONCLUSION: Our results provide molecular insights into CDZ-induced dynamics and structural changes of CaM leading to its inhibition and open the way to the rational design of more selective CaM antagonists. Calmidazolium is a potent and widely used inhibitor of calmodulin, a major mediator of calcium-signaling in eukaryotic cells. Structural characterization of calmidazolium-binding to calmodulin reveals that it triggers open-to-closed conformational changes similar to those induced by calmodulin-binding peptides derived from enzyme targets. These results provide molecular insights into CDZ-induced dynamics and structural changes of CaM leading to its inhibition and open the way to the rational design of more selective CaM antagonists.
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Calcio , Calmodulina , Calcio/metabolismo , Calmodulina/química , Calmodulina/metabolismo , Imidazoles , Unión Proteica , Dispersión del Ángulo Pequeño , Difracción de Rayos XRESUMEN
Facial movements of others during verbal and social interaction are often too rapid to be faced and/or processed in time by numerous children and adults with autism spectrum disorder (ASD), which could contribute to their face-to-face interaction peculiarities. We wish here to measure the effect of reducing the speed of one's facial dynamics on the visual exploration of the face by children with ASD. Twenty-three children with ASD and 29 typically-developing control children matched for chronological age passively viewed a video of a speaker telling a story at various velocities, i.e., a real-time speed and two slowed-down speeds. The visual scene was divided into four areas of interest (AOI): face, mouth, eyes, and outside the face. With an eye-tracking system, we measured the percentage of total fixation duration per AOI and the number and mean duration of the visual fixations made on each AOI. In children with ASD, the mean duration of visual fixations on the mouth region, which correlated with their verbal level, increased at slowed-down velocity compared with the real-time one, a finding which parallels a result also found in the control children. These findings strengthen the therapeutic potential of slowness for enhancing verbal and language abilities in children with ASD.
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Trastorno del Espectro Autista , Adulto , Niño , Tecnología de Seguimiento Ocular , Fijación Ocular , Humanos , Boca , HablaRESUMEN
A paralisia periódica hipocalêmica tireotóxica é uma complicação rara do hipertireoidismo. Caracteriza-se por episódios de fraqueza muscular recorrente, associado à tireotoxicose e hipocalemia. Ocorre frequentemente em pacientes do sexo masculino e de origem asiática. Nesse contexto, o objetivo deste estudo é descrever o relato de caso de um paciente acometido por paralisia periódica hipocalêmica tireotóxica com redução acentuada da qualidade de vida e internações recorrentes devido a quadro agudo de tetraparesia flácida ascendente associado a hipocalemia grave por não adesão ao tratamento do hipertireoidismo. A paralisia periódica hipocalêmica tireotóxica apresenta evolução favorável quando reconhecida e tratada com controle inicial dos sintomas para normalização sérica do potássio e posterior resolução do quadro tireotóxico.
Thyrotoxic hypokalemic periodic paralysis is a rare complication of hyperthyroidism. The issue has been characterized by episodes of recurrent muscle weakness associated with thyrotoxicosis and hypokalemia. It occurs most often in male patients of Asian origin. This study aims on describing the case report of a patient affected by thyrotoxic hypokalemic periodic paralysis with intense reduction in life quality and recurrent hospitalizations due to ascending acute flaccid tetraparesis associated with severe hypokalemia due to non-adherence to treatment of hyperthyroidism. Thyrotoxic hypokalemic periodic paralysis presents a favorable evolution when identified and treated with initial symptom control for serum potassium normalization and subsequent resolution of the thyroid toxicity.
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Humanos , Masculino , Adulto , Tirotoxicosis , Parálisis Periódica Hipopotasémica , Potasio , Glándula Tiroides , Debilidad Muscular , Pueblo Asiatico , Hipertiroidismo , HipopotasemiaRESUMEN
BACKGROUND: Transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex (dlPFC) might be a promising treatment strategy for depression. As disturbances in psychomotor activity are one of the key features of unipolar depression are, we aimed to evaluate the behavioral effects of ten tDCS sessions over a 5-day period on psychomotor retardation in depressed patients. METHODS: Twenty-three treatment-resistant depressed patients received either active or sham anodal tDCS to the left dorsolateral prefrontal cortex (2 mA, 10 sessions over 1 week). Psychomotor functioning was registered by means of observer ratings (Salpêtrière Retardation Rating Scale-SRRS) and objective measures (kinematical analysis of movements, automatic imitation). RESULTS: tDCS sessions resulted in improvements on SRRS scores, although active tDCS was not significantly superior to sham tDCS on the kinematical parameters. Furthermore, no general additional antidepressant effect of tDCS was observed. The relatively small sample size and the short periods of observation should be considered when interpreting these results. CONCLUSION: tDCS did not induce a clinically relevant effect on psychomotor function in active and sham stimulation groups.
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BACKGROUND: In view of population aging, a better knowledge of factors influencing the type of long-term care (LTC) among older adults is necessary. Previous studies reported a close relationship between incontinence and institutionalization, but little is known on opinions of older citizens regarding the most appropriate place of care. This study aimed at evaluating the impact of urine and/or fecal incontinence on preferences of community-dwelling older citizens. METHODS: We derived data from the Lausanne cohort 65+, a population-based study of individuals aged from 68 to 82 years. A total of 2974 community-dwelling persons were interviewed in 2017 on the most appropriate place of LTC delivery for three vignettes displaying a fixed level of disability with varying degrees of incontinence (none, urinary, urinary and fecal). Multinomial logistic regression analyses explored the effect of respondents' characteristics on their opinion according to Andersen's model. RESULTS: The level of incontinence described in vignettes strongly determined the likelihood of considering institutional care as most appropriate. Respondents' characteristics such as age, gender, educational level, being a caregiver, knowledge of shelter housing or feeling supported by family influenced LTC choices. Self-reported incontinence and other indicators of respondents' need, however, had no significant independent effect. CONCLUSION: Among older community-dwelling citizens, urinary and fecal incontinence play a decisive role in the perception of a need for institutionalization. Prevention and early initiation of support for sufferers may be a key to prevent this need and ensure familiar surrounding as long as possible.
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Cuidados a Largo Plazo , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Incontinencia Fecal/diagnóstico , Incontinencia Fecal/epidemiología , Incontinencia Fecal/terapia , Femenino , Humanos , Vida Independiente , Masculino , Encuestas y Cuestionarios , Incontinencia Urinaria/diagnóstico , Incontinencia Urinaria/epidemiología , Incontinencia Urinaria/terapiaRESUMEN
BACKGROUND: Numerous studies have attempted to identify predictors of institutionalization in the general population. Gender studies have led to inconsistent results. Some authors argued that older women were more likely than older men to use long-term care services, while others failed to highlight a specific gender effect on the use of long-term care services. The aim of this study was to assess the effects of gender on the preferences of older citizens for long-term care using a panel of disability situations. METHODS: We used a set of ten vignettes displaying disability situations with or without an able-bodied spouse present and used a population-based survey to inquire about appropriate long-term care. Participants were 3102 community-dwelling persons aged 68-83 years included in the representative Lausanne cohort 65+ study in January 2017. Multinomial logistic regression analyses were used to explore the effect of gender on long-term care choices by older men and women, controlling for the respondent's age and living arrangement. RESULTS: The respondents' choices shifted toward institutionalization when the disorder severity increased in vignettes and when there was no spouse able to help. Men were more likely to choose a home setting with caregiving only by spouse even when the level of disability increased. Women chose help from professionals, sheltered homes, or institutionalization more quickly than men. CONCLUSIONS: Exploring gender preferences for long-term care arrangements is critical for improving and planning long-term care services.
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Vida Independiente , Cuidados a Largo Plazo , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Institucionalización , Masculino , Características de la Residencia , Caracteres SexualesRESUMEN
OBJECTIVE: Several studies have demonstrated saccadic eye movement (SEM) abnormalities in Alzheimer's disease (AD) when patients performed prosaccade (PS) and antisaccade (AS) tasks. Some studies have also showed that SEM abnormalities were correlated with dementia rating tests such as the Mini Mental State Evaluation (MMSE). Therefore, it has been suggested that SEMs could provide useful information for diagnosis. However, little is known about predictive saccades (PreS)-saccades triggered before or very quickly after stimuli appearance-and their relationships with cognition in AD. Here, we aimed to examine the relationships between our usual dementia screening tests and SEM parameters in PS, AS, and also PreS task. METHOD: We compared SEMs in 20 patients suffering from AD and in 35 healthy older adults (OA) in PS, AS, and PreS task. All participants also completed a neuropsychological evaluation. RESULTS: We showed that AD patients had higher latency and latency variability regardless the tasks, and also higher AS cost, in comparison with OA. Moreover, AD patients made more uncorrected AS and took more time-to-correct incorrect AS. In PreS task, AD patients showed higher gain and gain variability than OA when they made anticipated saccades. Close relationships were found between the majority of SEM variables in PS, AS, and PreS tasks and dementia screening tests, especially the MMSE and episodic memory measures. CONCLUSION: Our findings, in agreement with previous studies, demonstrated that AD affects several SEM parameters. SEM abnormalities may reflect selective and executive-attention impairments in AD.
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Enfermedad de Alzheimer/fisiopatología , Movimientos Sacádicos/fisiología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/psicología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Desempeño PsicomotorRESUMEN
While there is a long history and tradition of behavioral research on basic motor skills in Down syndrome (DS), there has been only limited research on handwriting ability. We analyzed the spatiotemporal features of handwriting produced by children and adults with DS (n = 24), and compared their productions with those of comparison groups matched for developmental (n = 24) or chronological (n = 24) age. Results indicated that the participants with DS performed an alphabet letter-writing task just as efficiently as the children of the same developmental age, in terms of the length, duration and speed of their handwriting, and the number and duration of their pauses. Our study highlights a substantial delay in the stages of writing acquisition.
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Desarrollo Infantil/fisiología , Discapacidades del Desarrollo/fisiopatología , Síndrome de Down/fisiopatología , Escritura Manual , Destreza Motora/fisiología , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
BACKGROUND: The analysis of eye movements (EM) by eye-tracking has been carried out for several decades to investigate mood regulation, emotional information processing, and psychomotor disturbances in depressive disorders. METHOD: A systematic review of all English language PubMed articles using the terms "saccadic eye movements" OR "eye-tracking" AND "depression" OR "bipolar disorders" was conducted using PRISMA guidelines. The aim of this review was to characterize the specific alterations of EM in unipolar and bipolar depression. RESULTS: Findings regarding psychomotor disturbance showed an increase in reaction time in prosaccade and antisaccade tasks in both unipolar and bipolar disorders. In both disorders, patients have been reported to have an attraction for negative emotions, especially for negative pictures in unipolar and threatening images in bipolar disorder. However, the pattern could change with aging, elderly unipolar patients disengaging key features of sad and neutral stimuli. METHODological limitations generally include small sample sizes with mixed unipolar and bipolar depressed patients. CONCLUSION: Eye movement analysis can be used to discriminate patients with depressive disorders from controls, as well as patients with bipolar disorder from patients with unipolar depression. General knowledge concerning psychomotor alterations and affective regulation strategies associated with each disorder can also be gained thanks to the analysis. Future directions for research on eye movement and depression are proposed in this review.
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OBJECTIVES: Although several reported studies have suggested that younger adults with depression display depression-related biases during the processing of emotional faces, there remains a lack of data concerning these biases in older adults. The aim of our study was to assess scanning behavior during the processing of emotional faces in depressed older adults. METHOD: Older adults with and without depression viewed happy, neutral or sad portraits during an eye movement recording. RESULTS: Depressed older adults spent less time with fewer fixations on emotional features than healthy older adults, but only for sad and neutral portraits, with no significant difference for happy portraits. CONCLUSION: These results suggest disengagement from sad and neutral faces in depressed older adults, which is not consistent with standard theoretical proposals on congruence biases in depression. Also, aging and associated emotional regulation change may explain the expression of depression-related biases. Our preliminary results suggest that information processing in depression consists of a more complex phenomenon than merely a general searching for mood-congruent stimuli or general disengagement from all kinds of stimuli. These findings underline that care must be used when evaluating potential variables, such as aging, which interact with depression and selectively influence the choice of relevant stimulus dimensions.
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Envejecimiento/fisiología , Trastorno Depresivo Mayor/fisiopatología , Emociones/fisiología , Expresión Facial , Reconocimiento Visual de Modelos/fisiología , Anciano , Anciano de 80 o más Años , Envejecimiento/psicología , Medidas del Movimiento Ocular , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Motor imagery is a potential tool to investigate action representation, as it can provide insights into the processes of action planning and preparation. Recent studies suggest that depressed patients present specific impairment in mental rotation. The present study was designed to investigate the influence of unipolar depression on motor imagery ability. METHODS: Fourteen right-handed patients meeting DSM-IV criteria for unipolar depression were compared to 14 matched healthy controls. Imagery ability was accessed by the timing correspondence between executed and imagined movements during a pointing task, involving strong spatiotemporal constraints (speed/accuracy trade-off paradigm). RESULTS: Compared to controls, depressed patients showed marked motor slowing on both actual and imagined movements. Furthermore, we observed greater temporal discrepancies between actual and mental movements in depressed patients than in healthy controls. Lastly, depressed patients modulated, to some extent, mental movement durations according to the difficulty of the task, but this modulation was not as strong as that of healthy subjects. CONCLUSION: These results suggest that unipolar depression significantly affects the higher stages of action planning and point out a selective decline of motor prediction.
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The primary aim of this study was to characterize oculomotor performances in elderly depressed patients. The second aim was to investigate whether cognitive inhibition measured by the antisaccade task was associated with a psychomotor retardation or rather with a more specific cognitive-motor inhibition deficit. Twenty patients with a major depressive disorder and forty-seven healthy subjects performed two eye movement tasks. Saccadic reaction time and error rates were analyzed in the prosaccade task to obtain basic parameters of eye movements. Saccade latency, error rates and correction rates were evaluated in the antisaccade task to investigate inhibition capacities. Performances were impaired in patients, who exhibited a higher reaction time and error rates compared to controls. The higher time cost of inhibition suggested that the reaction time was not related to global psychomotor retardation alone. The higher time cost of inhibition could be explained by a specific alteration of inhibition processes evaluated by the antisaccade task. These changes were associated with the severity of depression. These findings provide a new perspective on cognitive inhibition in elderly depressed patients and could have important clinical implications for our understanding of critical behaviors involving deficits in inhibitory processes in the elderly.