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Abstract Background Craniopharyngioma is a rare condition in children, but it is the most frequent tumor that occurs in the hypothalamic pituitary region. Chemical meningitis has been described as an uncommon postoperative complication, but no chemical meningitis due to a spontaneous rupture leading to craniopharyngioma diagnosis in children has been reported. Case presentation This is a case of a 13-year-old boy presenting with fever, vomiting and headache for two days. The CT scan revealed a suprasellar lesion, and lumbar puncture showed aseptic meningitis. The cerebral MRI suggested a craniopharyngioma and the cerebrospinal fluid cholesterol concentration was abnormally high. A thorough medical history indicated some visual disturbance, which improved at the onset of meningitis, and an inflection of the growth curve. The anatomopathological analysis of the tumor confirmed the diagnosis of craniopharyngioma. Conclusions This case is the first to report the discovery of a craniopharyngioma with meningoencephalitis caused by the rupture of a craniopharyngioma cyst in a child. Diagnosis was facilitated by determining the cholesterol level in the cerebrospinal fluid, as well as fine anamnesis to identify visual and growth disturbances.

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Background. Temporal variability in fish reproductive features is influenced by environmental and spatial variations. Given the wide distribution of northern pike, Esox lucius Linnaeus, 1758, in the northern hemisphere, important reproductive features such as the initiation of the spawning activity are likely to vary with latitudinal gradients. The overall goal of the presently reported study was to answer basic questions regarding the reproductive biology of the pike and to discuss changes in the timing of the onset of spawning activity in relation to geographical locations and the water temperature in the Anzali Wetland compared to higher latitudes. Materials and methods. Monthly samples (537 specimens in total) were collected from the Anzali Wetland (southwest of the Caspian Sea) from July 2012 through July 2013. Samples were macro- and microscopically examined, and their maturity stages were identified, so that spawning season, monthly distribution of maturity stages, oocytes development, spawning strategy, length at 50% maturity, and fecundity were estimated. Results. The gonadosomatic index, oocyte size-frequency distribution, and histological examination suggested a relatively short spawning season, from February through March. The short annual spawning period and the oocyte size-frequency distribution demonstrated that pike is a total spawner with group synchronous oocyte development. The length at 50% maturity was 28.5 and 33.9 cm FL for males and females, respectively. Absolute fecundity values ranged from 4423 to 48 471 oocytes, with mean (± standard error) of 16 481 ± 2705 oocytes and the relative fecundity was estimated as 26.9 ± 1.6 oocytes per gram of mature female. Conclusion. The most important findings of this study are: the earlier initiation and relatively shorter duration of the reproductive activities of pike in the south Caspian region compared to northern geographical regions. The results emphasize the need for specific management strategies based on seasonal measures for pike such as: fish size limits, limitation of catches during the spawning season, limitation of the boat number, and closure of the spawning area during spawning months. [ABSTRACT FROM AUTHOR]

The proteins secreted by a particular type of cell, the secretome, play important roles in the regulation of many physiological processes via paracrine/autocrine mechanisms, and they are of increasing interest to help understanding rare diseases and to identify potential biomarkers and therapeutic targets. To facilitate ongoing research involving secreted proteins, we revisited cell culture protocols and whole secreted protein enrichment protocols. A reliable method for culturing and precipitating secreted protein from patient-derived fibroblast conditioned-medium was established. The method is based on the optimization of cell confluency and incubation time conditions. The well-established carrier-based TCA-DOC protein precipitation method was consistently found to give higher protein recovery yield. According to our results, we therefore propose that protein enrichment should be performed by TCA-DOC precipitation method 48 hours at 95% of confluence in a serum-deprived culture medium. Given the importance of secreted proteins as a source to elucidate the pathogenesis of rare diseases, especially neurological disorders, this approach may help to discover novel candidate biomarkers with potential clinical significance.

Movement generation has been hypothesized to rely on a modular organization of muscle activity. Crucial to this hypothesis is the ability to perform reliably a variety of motor tasks by recruiting a limited set of modules and combining them in a task-dependent manner. Thus far, existing algorithms that extract putative modules of muscle activations, such as Nonnegative Matrix Factorization (NMF), identify modular decompositions that maximize the reconstruction of the recorded EMG data. Typically, the functional role of the decompositions, i.e. task accomplishment, is only assessed a posteriori. However, as motor actions are defined in task space, we suggest that motor modules should be computed in task space too. In this study, we propose a new module extraction algorithm, named DsNM3F, that uses task information during the module identification process. DsNM3F extends our previous space-by-time decomposition method (the so-called sNM3F algorithm, which could assess task performance only after having computed modules) to identify modules gauging between two complementary objectives: reconstruction of the original data and reliable discrimination of the performed tasks. We show that DsNM3F recovers the task dependence of module activations more accurately than sNM3F. We also apply it to electromyographic signals recorded during performance of a variety of arm pointing tasks and identify spatial and temporal modules of muscle activity that are highly consistent with previous studies. DsNM3F achieves perfect task categorization without significant loss in data approximation when task information is available and generalizes as well as sNM3F when applied to new data. These findings suggest that the space-by-time decomposition of muscle activity finds robust task-discriminating modular representations of muscle activity and that the insertion of task discrimination objectives is useful for describing the task modulation of module recruitment.

We have previously reported Lvm1 as a quantitative trait locus (QTL) on chromosome 13 (chr13) that links to cardiac left ventricular mass (LVM) in a panel of AxB/BxA mouse recombinant inbred strains (RIS). When performing a gene expression QTL (eQTL) analysis, we detected 33 cis-eQTLs that correlated with LVM. Among the latter, a group of 8 cis-eQTLs clustered in a genomic region smaller than 6 Mb and surrounding the Lvm1 peak on chr13. Co-variant analysis indicated that all 8 genes correlated with the phenotype in a causal rather than a reactive fashion, a finding that (despite its functional interest) did not provide grounds to prioritize any of these candidate genes. As a complementary approach, we performed weighted gene co-expression network analysis, which allowed us to detect 49 modules of highly connected genes. The module that correlated best with LVM: 1) showed linkage to a module QTL whose boundaries matched closely those of the phenotypic Lvm1 QTL on chr13; 2) harbored a disproportionately high proportion of genes originating from a small genomic region on chromosome 13 (including the 8 previously detected cis-eQTL genes); 3) contained genes that, beyond their individual level of expression, correlated with LVM as a function of their inter-connectivity; and 4) showed increased abundance of polymorphic insertion-deletion elements in the same region. Taken together, these data suggest that a domain on chromosome 13 constitutes the biologic principle responsible for the organization and linkage of the gene co-expression module, and indicate a mechanism whereby genetic variants within chromosome domains may associate to phenotypic changes via coordinate changes in the expression of several genes. One other possible implication of these findings is that candidate genes to consider as contributors to a particular phenotype should extend further than those that are closest to the QTL peak.

Linguistic relativity theory has received empirical support in domains such as colour perception and object categorisation. It is unknown however, whether relations between words idiosyncratic to language impact nonverbal representations and conceptualisations. For instance, would one consider the concepts of horse and sea as related were it not for the existence of the compound seahorse? Here, we investigated such arbitrary conceptual relationships using a non-linguistic picture relatedness task in participants undergoing event-related brain potential recordings. Picture pairs arbitrarily related because of a compound and presented in the compound order elicited N400 amplitudes similar to unrelated pairs. Surprisingly, however, pictures presented in the reverse order (as in the sequence horse – sea) reduced N400 amplitudes significantly, demonstrating the existence of a link in memory between these two concepts otherwise unrelated. These results break new ground in the domain of linguistic relativity by revealing predicted semantic associations driven by lexical relations intrinsic to language.

Muscle synergies have been hypothesized to be the building blocks used by the central nervous system to generate movement. According to this hypothesis, the accomplishment of various motor tasks relies on the ability of the motor system to recruit a small set of synergies on a single-trial basis and combine them in a task-dependent manner. It is conceivable that this requires a fine tuning of the trial-to-trial relationships between the synergy activations. Here we develop an analytical methodology to address the nature and functional role of trial-to-trial correlations between synergy activations, which is designed to help to better understand how these correlations may contribute to generating appropriate motor behavior. The algorithm we propose first divides correlations between muscle synergies into types (noise correlations, quantifying the trial-to-trial covariations of synergy activations at fixed task, and signal correlations, quantifying the similarity of task tuning of the trial-averaged activation coefficients of different synergies), and then uses single-trial methods (task-decoding and information theory) to quantify their overall effect on the task-discriminating information carried by muscle synergy activations. We apply the method to both synchronous and time-varying synergies and exemplify it on electromyographic data recorded during performance of reaching movements in different directions. Our method reveals the robust presence of information-enhancing patterns of signal and noise correlations among pairs of synchronous synergies, and shows that they enhance by 9-15% (depending on the set of tasks) the task-discriminating information provided by the synergy decompositions. We suggest that the proposed methodology could be useful for assessing whether single-trial activations of one synergy depend on activations of other synergies and quantifying the effect of such dependences on the task-to-task differences in muscle activation patterns.

In this paper we review the works related to muscle synergies that have been carried-out in neuroscience and control engineering. In particular, we refer to the hypothesis that the central nervous system (CNS) generates desired muscle contractions by combining a small number of predefined modules, called muscle synergies. We provide an overview of the methods that have been employed to test the validity of this scheme, and we show how the concept of muscle synergy has been generalized for the control of artificial agents. The comparison between these two lines of research, in particular their different goals and approaches, is instrumental to explain the computational implications of the hypothesized modular organization. Moreover, it clarifies the importance of assessing the functional role of muscle synergies: although these basic modules are defined at the level of muscle activations (input-space), they should result in the effective accomplishment of the desired task. This requirement is not always explicitly considered in experimental neuroscience, as muscle synergies are often estimated solely by analyzing recorded muscle activities. We suggest that synergy extraction methods should explicitly take into account task execution variables, thus moving from a perspective purely based on input-space to one grounded on task-space as well.

A long standing hypothesis in the neuroscience community is that the CNS generates the muscle activities to accomplish movements by combining a relatively small number of stereotyped patterns of muscle activations, often referred to as muscle synergies. Different definitions of synergies have been given in the literature. The most well-known are those of synchronous, time-varying and temporal muscle synergies. Each one of them is based on a different mathematical model used to factor some EMG array recordings collected during the execution of variety of motor tasks into a well-determined spatial, temporal or spatio-temporal organization. This plurality of definitions and their separate application to complex tasks have so far complicated the comparison and interpretation of the results obtained across studies, and it has always remained unclear why and when one synergistic decomposition should be preferred to another one. By using well-understood motor tasks such as elbow flexions and extensions, we aimed in this study to clarify better what are the motor features characterized by each kind of decomposition and to assess whether, when and why one of them should be preferred to the others. We found that three temporal synergies, each one of them accounting for specific temporal phases of the movements could account for the majority of the data variation. Similar performances could be achieved by two synchronous synergies, encoding the agonist-antagonist nature of the two muscles considered, and by two time-varying muscle synergies, encoding each one a task-related feature of the elbow movements, specifically their direction. Our findings support the notion that each EMG decomposition provides a set of well-interpretable muscle synergies, identifying reduction of dimensionality in different aspects of the movements. Taken together, our findings suggest that all decompositions are not equivalent and may imply different neurophysiological substrates to be implemented.

Muscle synergies, i.e. invariant coordinated activations of groups of muscles, have been proposed as building blocks that the central nervous system uses to construct the patterns of muscle activity utilized for executing movements. Several efficient dimensionality reduction algorithms that extract putative synergies from electromyographic (EMG) signals have been developed. Typically, the quality of synergy decompositions is assessed by computing the variance accounted for (VAF). Yet, little is known about the extent to which the combination of those synergies encodes task-discriminating variations of muscle activity in individual trials. To address this question, here we conceive and develop a novel computational framework to evaluate muscle synergy decompositions in task space. Unlike previous methods considering the total variance of muscle patterns (VAF based metrics), our approach focuses on variance discriminating execution of different tasks. The procedure is based on single-trial task decoding from muscle synergy activation features. The task decoding based metric evaluates quantitatively the mapping between synergy recruitment and task identification and automatically determines the minimal number of synergies that captures all the task-discriminating variability in the synergy activations. In this paper, we first validate the method on plausibly simulated EMG datasets. We then show that it can be applied to different types of muscle synergy decomposition and illustrate its applicability to real data by using it for the analysis of EMG recordings during an arm pointing task. We find that time-varying and synchronous synergies with similar number of parameters are equally efficient in task decoding, suggesting that in this experimental paradigm they are equally valid representations of muscle synergies. Overall, these findings stress the effectiveness of the decoding metric in systematically assessing muscle synergy decompositions in task space.

Can we accept the statistics provided by the Ministry of Health, which uses large computerized databases? Through MEDECHO, the Ministry provides to hospital managers, reports cards on different interventions. These reports compare different hospitals performances. Surgeons involved in the process hesitate to accept this information. Using the results of the performance of cholecystectomy provided by this system (Gr: A), we compared the same cohort (1 April–31 December 1996 = 346 cholecystectomies) but using specific criteria determined as relevant to our surgeons (Gr: B). The rate of complication gives a crude aftermath and no attempt was used to adjust for severity. The MEDECHO data are adjusted for severity. The global rate of complications is similar Gr: A 11%, Gr: B 12%. Major complication rate for pulmonary embolism, hemorrhage and biliary duct trauma are identical. The rate of surgical site infection is higher in Gr: B (5% vs. 2%). The patients are seen in the outpatient clinic and these observations are not included by the analytical system unless the patient has been readmitted. For our hospital, the MEDECHO data are valid and reliable even though they underestimated the wound infection rate. These results could be explained by an appropriate interpretation of the code system by the archivist and by the surgeons’ precision to complete the summary sheet of hospitalization. We can conclude that these data can be used as a means to evaluate the quality of outcome of a surgical service. [Copyright &y& Elsevier]

Pancreatic islet transplantation is a promising treatment for type 1 diabetes, but the survival and function of transplanted islets are hindered by the loss of extracellular matrix (ECM) during islet isolation and by low oxygenation upon implantation. This study aimed to evaluate the impact of hypoxia on ECM using a cutting-edge imaging approach based on tissue clearing and 3D microscopy. Human and rat islets were cultured under normoxic (O 2 21%) or hypoxic (O 2 1%) conditions. Immunofluorescence staining targeting insulin, glucagon, CA9 (a hypoxia marker), ECM proteins (collagen 4, fibronectin, laminin), and E-cadherin (intercellular adhesion protein) was performed on fixed whole islets. The cleared islets were imaged using Light Sheet Fluorescence Microscopy (LSFM) and digitally analyzed. The volumetric analysis of target proteins did not show significant differences in abundance between the experimental groups. However, 3D projections revealed distinct morphological features that differentiated normoxic and hypoxic islets. Under normoxic conditions, ECM could be found throughout the islets. Hypoxic islets exhibited areas of scattered nuclei and central clusters of ECM proteins, indicating central necrosis. E-cadherin was absent in these areas. Our results, demonstrating a diminution of islets' functional mass in hypoxia, align with the functional decline observed in transplanted islets experiencing low oxygenation after grafting. This study provides a methodology combining tissue clearing, multiplex immunofluorescence, Light Sheet Fluorescence Microscopy, and digital image analysis to investigate pancreatic islet morphology. This 3D approach allowed us to highlight ECM organizational changes during hypoxia from a morphological perspective.

Background: The conventional method of drug development in oncology typically progresses through phase I, phase II and randomized phase III trials. Nevertheless, some recent drug approvals for head and neck cancer (HNC) relied on findings from single-arm phase II trials. This underscores the significance of disease-specific phase I trials as a crucial step in exploring new drugs for HNC patients. The purpose of this review is to present the currently available data of phase I clinical trials conducted in HNC and to provide an overview of ongoing therapeutic trends in HNC., Methods: We performed a scoping review of phase I trials evaluating single-agent treatments specifically designed for HNC patients. The PubMed database was searched using "(phase I) AND (head and neck)". To ensure exhaustiveness, we also performed a search from the American Society of Clinical Oncology, European Society for Medical Oncology and American Association for Cancer Research websites., Results: We screened 1,134 articles and selected 29 trials that met eligibility criteria, published between 1994 and 2023, for a total of 741 patients. Twenty-one trials comprised patients with different sites of HNSCC and only 8 trials (27%) focused on a specified subsite of head and neck. Most of trials investigated treatments in recurrent/metastatic (R/M) settings (86%). Immunotherapeutic agents were the most examined followed by targeted agents, cytotoxic drugs and "others" including a nanoparticle, a therapeutic gene, a fusion protein and a modulator of gene expression. Among trials reporting activity for R/M head and neck patients (n=23), the global median overall response rate (ORR) was 12% and four trials (17%) did not report any response. The incidence of grade 3/4 treatment-related adverse events (TRAEs) was low (7%). However, in seven trials safety results are not clearly assessable from the published data., Conclusions: Phase I trials of single agents designed for head and neck patients were generally safe but with a low ORR. Future development of new drugs dedicated for HNC patients that can more accurately reflect the heterogeneity of HNC and provide more detailed subgroup analyses is warranted.

Inflammasomes are multiprotein platforms that control caspase-1 activation, which process the inactive precursor forms of the inflammatory cytokines IL-1β and IL-18, leading to an inflammatory type of programmed cell death called pyroptosis. Studying inflammasome-driven processes, such as pyroptosis-induced cell swelling, under controlled conditions remains challenging because the signals that activate pyroptosis also stimulate other signaling pathways. We designed an optogenetic approach using a photo-oligomerizable inflammasome core adapter protein, apoptosis-associated speck-like containing a caspase recruitment domain (ASC), to temporally and quantitatively manipulate inflammasome activation. We demonstrated that inducing the light-sensitive oligomerization of ASC was sufficient to recapitulate the classical features of inflammasomes within minutes. This system showed that there were two phases of cell swelling during pyroptosis. This approach offers avenues for biophysical investigations into the intricate nature of cellular volume control and plasma membrane rupture during cell death.

Understanding the ecological impacts of viruses on natural and engineered ecosystems relies on the accurate identification of viral sequences from community sequencing data. To maximize viral recovery from metagenomes, researchers frequently combine viral identification tools. However, the effectiveness of this strategy is unknown. Here, we benchmarked combinations of six widely used informatics tools for viral identification and analysis (VirSorter, VirSorter2, VIBRANT, DeepVirFinder, CheckV, and Kaiju), called "rulesets." Rulesets were tested against mock metagenomes composed of taxonomically diverse sequence types and diverse aquatic metagenomes to assess the effects of the degree of viral enrichment and habitat on tool performance. We found that six rulesets achieved equivalent accuracy [Matthews Correlation Coefficient (MCC) = 0.77, P adj ≥ 0.05]. Each contained VirSorter2, and five used our "tuning removal" rule designed to remove non-viral contamination. While DeepVirFinder, VIBRANT, and VirSorter were each found once in these high-accuracy rulesets, they were not found in combination with each other: combining tools does not lead to optimal performance. Our validation suggests that the MCC plateau at 0.77 is partly caused by inaccurate labeling within reference sequence databases. In aquatic metagenomes, our highest MCC ruleset identified more viral sequences in virus-enriched (44%-46%) than in cellular metagenomes (7%-19%). While improved algorithms may lead to more accurate viral identification tools, this should be done in tandem with careful curation of sequence databases. We recommend using the VirSorter2 ruleset and our empirically derived tuning removal rule. Our analysis provides insight into methods for in silico viral identification and will enable more robust viral identification from metagenomic data sets., Importance: The identification of viruses from environmental metagenomes using informatics tools has offered critical insights in microbial ecology. However, it remains difficult for researchers to know which tools optimize viral recovery for their specific study. In an attempt to recover more viruses, studies are increasingly combining the outputs from multiple tools without validating this approach. After benchmarking combinations of six viral identification tools against mock metagenomes and environmental samples, we found that these tools should only be combined cautiously. Two to four tool combinations maximized viral recovery and minimized non-viral contamination compared with either the single-tool or the five- to six-tool ones. By providing a rigorous overview of the behavior of in silico viral identification strategies and a pipeline to replicate our process, our findings guide the use of existing viral identification tools and offer a blueprint for feature engineering of new tools that will lead to higher-confidence viral discovery in microbiome studies., Competing Interests: The authors declare no conflict of interest.

Tumor acidosis is associated with increased invasiveness and drug resistance. Here, we take an unbiased approach to identify vulnerabilities of acid-exposed cancer cells by combining pH-dependent flow cytometry cell sorting from 3D colorectal tumor spheroids and transcriptomic profiling. Besides metabolic rewiring, we identify an increase in tetraploid cell frequency and DNA damage response as consistent hallmarks of acid-exposed cancer cells, supported by the activation of ATM and ATR signaling pathways. We find that regardless of the cell replication error status, both ATM and ATR inhibitors exert preferential growth inhibitory effects on acid-exposed cancer cells. The efficacy of a combination of these drugs with 5-FU is further documented in 3D spheroids as well as in patient-derived colorectal tumor organoids. These data position tumor acidosis as a revelator of the therapeutic potential of DNA repair blockers and as an attractive clinical biomarker to predict the response to a combination with chemotherapy., (© 2024. The Author(s).)

Introduction: The Coronavirus (COVID-19) pandemic and its associated health restrictions have harmed the population psychologically. We aimed to compare the post-traumatic stress disorder (PTSD) symptoms and Quality of Life (QoL) in older French patients with cancer to the younger ones., Materials and Methods: This longitudinal multicenter study named COVIPACT began in April 2020 during the first French lockdown and has included 579 outpatients receiving treatment for a solid or hematological malignancy. Data were collected every three months, namely at the first release period (M3), at the second lockdown (M6), at the second release period (M9), and finally at the last curfew period (M12) in France. Standardized validated self-questionnaires were used to assess PTSD symptoms (using the Event Scale-Revised self-questionnaire), insomnia (through the Insomnia Severity Index questionnaire), QoL (using the Functional Assessment of Cancer Therapy - General questionnaire), and cognitive complaints (through the Functional Assessment of Cancer Therapy - Cognition questionnaire). Student (or Wilcoxon) tests and Chi-squared tests were used for continuous or discrete variables, respectively. We conducted linear mixed model to study the change during follow-up., Results: Out of 579 included patients, 157 (27%) were ≥ 70 years old at baseline, of whom 104 participated in the longitudinal study. At baseline, older patients reported fewer PTSD symptoms (17% versus 23%, p = .06), insomnia (17% versus 27%, p = .02), and cognitive complaint (3% versus 16%, p < .01) than younger patients. QoL at baseline was similar between age subgroups. We observed no significant difference in the trajectory of PTSD symptoms, insomnia, or emotional well-being between both groups during the follow-up. Cognitive complaints were lower at baseline in older patients but steadily increased during the follow-up and reached the same level as younger patients at one year., Discussion: One in five older patients reported PTSD symptoms, evolving similarly to younger patients during the first year of the COVID-19 pandemic. While cognitive complaints tend to recover in a bell-shaped curve at one year in younger patients, the trend is increasing in older ones. Screening for PTSD symptoms and late cognitive impairment should be given special attention in older patients., Trial Registration: Clinicaltrials.gov identifier: NCT04366154., Competing Interests: Declaration of Competing Interest Authors declare no conflict of interest with this work., (Copyright © 2023. Published by Elsevier Ltd.)

Importance: Endocrine therapies (ETs) and inhibitors of cyclin-dependent kinases-4/6 (iCDK4/6s) are a standard treatment in breast cancer. However, data on potential neurocognitive impacts remain inconsistent for ET and are scarce for iCDK4/6s. Objective: To evaluate whether ET and iCDK4/6s are associated with neurocognitive impairment (NCI). Methods: We used observational, real-world cases of NCI from the World Health Organization's database VigiBase ® to perform disproportionality analysis. Cases were defined as any symptom of NCI in females treated with ETs or iCDK4/6s. The study period was from the date of the first adverse event reported in VigiBase ® with iCDK4/6s (1 January 2014) until the date of data extraction (16 March 2022). In our primary analysis, we calculated the reporting odds ratio (ROR) adjusted for age to identify a potential association between NCI and individual ETs in isolation or in combination with iCDK4/6s. We also performed subgroup analyses by the NCI class. Results: We identified 2.582 and 1.943 reports of NCI associated with ETs and iCDK4/6s, respectively. NCI was significantly associated with each ET [anastrozole: n = 405, aROR = 1.52 (95% CI: 1.37-1.67); letrozole: n = 741, aROR = 1.37 (95% CI: 1.27-1.47); exemestane: n = 316, aROR = 1.37 (95% CI: 1.22-1.53); tamoxifen: n = 311, aROR = 1.25 (95% CI: 1.12-1.40); and fulvestrant: n = 319, aROR = 1.19 (95% CI: 1.06-1.33)] and only with palbociclib for iCDK4/6s [ n = 1,542, aROR = 1.41 (95% CI: 1.34-1.48)]. Conclusion: These findings suggest that in females treated for breast cancer, all ETs may be associated with NCI. However, amongst iCDK4/6s, NCI may be specific to palbociclib. NCI most frequently involved learning and memory as well as language. Neurocognitive impact of treatments requires better consideration and management., Competing Interests: FJ has received consulting fees from AstraZeneca, GSK, Janssen, and Ipsen and declares honoraria for lectures and scientific boards from AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Prevost, Chretien, Minoc, Dolladille, Da-Silva, Nehme, Joly, Lelong-Boulouard and Bastien.)

Introduction: COVID-19 outbreak rapidly spread since early 2020 leading to the implementation of nationwide lockdowns. To cope with this sudden change, management guidelines were quickly published to adapt oncological care, with potential impact on cancer outcomes., Methods: We conducted a retrospective comparative cohort study to assess the impact of the COVID-19 outbreak in 2020 on cancer outcomes in metastatic patients. Two cohorts of metastatic patients receiving intravenous (iv) therapy in a French oncological day care hospital were assessed: a 2020 cohort during the first French lockdown, and a 2018 historical cohort before the COVID-19 pandemic. We performed a propensity score analysis to match patients from the two cohorts. After one-year follow-up, we compared progression-free survival (PFS) and overall survival (OS) between cohorts. Adaptations of medical oncological treatments in 2020 were also analysed., Results: The 376 patients of the 2020 cohort were matched with 376 of the 2018 cohort. No SARS-CoV-2 infection was observed in the 2020 cohort. The adjusted PFS was significantly shorter in 2020 compared to 2018 (HR = 1.23; 95% CI: 1.03-1.46), as well as among patients without treatment adaptation compared to matched patients of the 2018 cohort (HR = 1.33; 95% CI: 1.10-1.61). We did not observe any significant difference of PFS among the group with treatment adaptations. OS was not significantly different., Conclusion: Metastatic cancer patients treated during the first lockdown had a higher risk of disease progression 1 year after COVID-19 outbreak. However, oncological treatment adaptations or SARS-CoV-2 infections do not explain these results. A longer follow-up is needed to observe the impact on OS., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Patients with cancer may be particularly vulnerable to psychological consequences of the COVID-19 pandemic. We studied the prevalence and evolution of posttraumatic stress symptoms (PTSS) in patients with cancer during the pandemic waves, and we investigated factors associated with high symptoms., Methods: COVIPACT is a 1-year longitudinal prospective study of French patients with solid/hematologic malignancies receiving treatment during the first nationwide lockdown. PTSS were measured every 3 months from April 2020 using the Impact of Event Scale-Revised. Patients also completed questionnaires on their quality of life, cognitive complaints, insomnia, and COVID-19 lockdown experience., Results: Longitudinal analyses involved 386 patients with at least one PTSS assessment after baseline (median age, 63 years; 76% female). Among them, 21.5% had moderate/severe PTSS during the first lockdown. The rate of patients reporting PTSS decreased at lockdown release (13.6%), increased again at second lockdown (23.2%), and slightly declined from the second release period (22.7%) to the third lockdown (17.5%). Patients were grouped into 3 trajectories of evolution. Most patients had stable low symptoms throughout the period, 6% had high baseline symptoms slowly decreasing over time, and 17.6% had moderate symptoms worsening during the second lockdown. Female sex, feeling socially isolated, worrying about COVID-19 infection, and using psychotropic drugs were associated with PTSS. PTSS were associated with impaired quality of life, sleep, and cognition., Conclusions: Approximately one-fourth of patients with cancer experienced high and persistent PTSS over the first year of the COVID-19 pandemic and may benefit from psychological support., Clinicaltrials: gov identifier: NCT04366154.

Background: Transverse myelitis (TM) has recently been associated by health authorities with Ad26.COV2.S (Janssen/Johnson & Johnson), one of the 5 US Food and Drug Administration (FDA) or European Medicines Agency (EMA) labeled severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. It is unknown whether a similar association exists for the other FDA or EMA labeled SARS-CoV-2 vaccines (BNT162b2 [Pfizer/BioNTech], mRNA-1273 [Moderna], ChAdOx1nCov-19 [Oxford-AstraZeneca], and NVX-CoV2373 [Novavax]). This study aimed to evaluate the association between SARS-CoV-2 vaccine class and TM., Methods: This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from VigiBase, the World Health Organization's pharmacovigilance database. We first conducted a disproportionality analysis with the information component (IC) using the reports of TM that occurred within 28 days following exposure to the FDA or EMA labeled SARS-CoV-2 vaccines, from December 1, 2020 (first adverse event related to a SARS-CoV-2 vaccine) to March 27, 2022. Second, we analyzed the clinical features of SARS-CoV-2 vaccine-associated TM cases reported in VigiBase., Results: TM was significantly associated both with the messenger ribonucleic acid (mRNA)-based (n = 364; IC 025  = 0.62) and vector-based (n = 136; IC 025  = 0.52) SARS-CoV-2 vaccines that are authorized by the FDA or the EMA., Conclusions: Findings from this observational, cross-sectional pharmacovigilance study showed that mRNA-based and vector-based FDA/EMA labeled SARS-CoV-2 vaccines can be associated with TM. However, because TM remains a rare event, with a previously reported rate of 0.28 cases per 1 million vaccine doses, the risk-benefit ratio in favor of vaccination against SARS-CoV-2 virus remains unchallenged. Rather, this study suggests that clinicians should consider the diagnosis of TM in patients presenting with early signs of spinal cord dysfunction after SARS-CoV-2 vaccination. ANN NEUROL 2022;92:1080-1089., (© 2022 American Neurological Association.)

Background: The COVID-19 pandemic may induce post-traumatic stress disorder (PTSD) symptoms among patients with cancer, who also face adaptations to their treatment. The authors assessed the occurrence of PTSD symptoms, investigated pandemic-induced adjustments in medical oncology practice in patients with cancer, and explored risk factors for PTSD and the association between PTSD symptoms, insomnia, and quality of life (QoL)., Methods: This prospective French study was conducted in patients with solid/hematologic tumors who were receiving medical treatment in the day care departments of 2 cancer centers during the lockdown. Adjustments to medical oncology practice were collected from medical records. PTSD (measured using the Impact of Event Scale-Revised), insomnia (measured using the Insomnia Severity Index), QoL (measured using the Functional Assessment of Cancer Therapy-General instrument), and cognitive complaints (measured using the Functional Assessment of Cancer Therapy-Cognitive Function instrument) were collected through validated questionnaires., Results: Clinical data and questionnaires were available for 734 and 576 patients, respectively. The median patient age was 64 years, and 69% of patients were women. Twenty-one percent of patients had PTSD. Twenty-seven percent (95% CI, 23%-30%) had an adjustment in their medical oncology program, including adjournments (29%), treatment interruptions (16%), modified treatment plans (27%), or adapted monitoring (27%). Women and patients experiencing an adjustment in oncology practice had a higher odds of PTSD (odds ratio= 2.10 [95% CI, 1.07-4.14] and 1.65 [95% CI, 1.03-2.63]; P < .05). PTSD symptoms were correlated with worse scores for QoL, cognition, and insomnia., Conclusions: Twenty-one percent of patients with cancer experienced PTSD symptoms associated with poor QoL during the first COVID-19-induced lockdown. Medical oncology practice was adjusted in approximately one-quarter of patients and was associated with the occurrence of PTSD symptoms. Psychosocial support should be offered in cancer centers to promote emotional resilience and avoid PTSD symptoms in patients., (© 2021 American Cancer Society.)

Tumor acidosis promotes disease progression through a stimulation of fatty acid (FA) metabolism in cancer cells. Instead of blocking the use of FAs by acidic cancer cells, we examined whether excess uptake of specific FAs could lead to antitumor effects. We found that n-3 but also remarkably n-6 polyunsaturated FA (PUFA) selectively induced ferroptosis in cancer cells under ambient acidosis. Upon exceeding buffering capacity of triglyceride storage into lipid droplets, n-3 and n-6 PUFA peroxidation led to cytotoxic effects in proportion to the number of double bonds and even more so in the presence of diacylglycerol acyltransferase inhibitors (DGATi). Finally, an n-3 long-chain PUFA-rich diet significantly delayed mouse tumor growth when compared with a monounsaturated FA-rich diet, an effect further accentuated by administration of DGATi or ferroptosis inducers. These data point out dietary PUFA as a selective adjuvant antitumor modality that may efficiently complement pharmacological approaches., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Metabolic plasticity in cancer cells makes use of metabolism-targeting agents very challenging. Drug-induced metabolic rewiring may, however, uncover vulnerabilities that can be exploited. We report that resistance to glycolysis inhibitor 3-bromopyruvate (3-BrPA) arises from DNA methylation in treated cancer cells and subsequent silencing of the monocarboxylate transporter MCT1. We observe that, unexpectedly, 3-BrPA-resistant cancer cells mostly rely on glycolysis to sustain their growth, with MCT4 as an essential player to support lactate flux. This shift makes cancer cells particularly suited to adapt to hypoxic conditions and resist OXPHOS inhibitors and anti-proliferative chemotherapy. In contrast, blockade of MCT4 activity in 3-BrPA-exposed cancer cells with diclofenac or genetic knockout, inhibits growth of derived spheroids and tumors in mice. This study supports a potential mode of collateral lethality according to which metabolic adaptation of tumor cells to a first-line therapy makes them more responsive to a second-line treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Epidemiological studies have shown that obese subjects have an increased risk of developing triple-negative breast cancer (TNBC) and an overall reduced survival. However, the relation between obesity and TNBC remains difficult to understand. We hypothesize that apelin, an adipokine whose levels are increased in obesity, could be a major factor contributing to both tumour growth and metastatization in TNBC obese patients. We observed that development of obesity under high-fat diet in TNBC tumour-bearing mice significantly increased tumour growth. By showing no effect of high-fat diet in obesity-resistant mice, we demonstrated the necessity to develop obesity-related disorders to increase tumour growth. Apelin mRNA expression was also increased in the subcutaneous adipose tissue and tumours of obese mice. We further highlighted that the reproduction of obesity-related levels of apelin in lean mice led to an increased TNBC growth and brain metastases formation. Finally, injections of the apelinergic antagonist F13A to obese mice significantly reduced TNBC growth, suggesting that apelinergic system interference could be an interesting therapeutic strategy in the context of obesity and TNBC., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Crosstalk between cancer-associated fibroblasts (CAFs) and colorectal cancer cells promotes tumor growth and contributes to chemoresistance. In this study, we assessed the sensitivity of a primary CAF cell line, CT5.3hTERT, to standard-of-care and alternative cytotoxic treatments. Paclitaxel (PTX) and acriflavine (ACF) were identified as the most promising molecules to inhibit CAF development. To allow the translational use of both drugs, we developed lipid nanocapsule (LNC) formulations for PTX and ACF. Finally, we mixed CAFs and tumor cell lines in a cocultured spheroid, and the effect of both drugs was investigated by histological analyses. We demonstrated CAF inhibition by LNC-ACF and whole tumor inhibition by LNC-PTX. Altogether, we proposed a new strategy to reduce CAF populations in the colorectal microenvironment that should be tested in vivo., 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 © 2020 Elsevier B.V. All rights reserved.)

Acidosis, a common characteristic of the tumor microenvironment, is associated with alterations in metabolic preferences of cancer cells and progression of the disease. Here we identify the TGF-β2 isoform at the interface between these observations. We document that acidic pH promotes autocrine TGF-β2 signaling, which in turn favors the formation of lipid droplets (LD) that represent energy stores readily available to support anoikis resistance and cancer cell invasiveness. We find that, in cancer cells of various origins, acidosis-induced TGF-β2 activation promotes both partial epithelial-to-mesenchymal transition (EMT) and fatty acid metabolism, the latter supporting Smad2 acetylation. We show that upon TGF-β2 stimulation, PKC-zeta-mediated translocation of CD36 facilitates the uptake of fatty acids that are either stored as triglycerides in LD through DGAT1 or oxidized to generate ATP to fulfill immediate cellular needs. We also address how, by preventing fatty acid mobilization from LD, distant metastatic spreading may be inhibited.