Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.

Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. SIGNIFICANCE: Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer. See related commentary by Frigo, p. 1742.

The gut microbiome-prostate cancer crosstalk is modulated by dietary polyunsaturated long-chain fatty acids.

The gut microbiota modulates response to hormonal treatments in prostate cancer (PCa) patients, but whether it influences PCa progression remains unknown. Here, we show a reduction in fecal microbiota alpha-diversity correlating with increase tumour burden in two distinct groups of hormonotherapy naïve PCa patients and three murine PCa models. Fecal microbiota transplantation (FMT) from patients with high PCa volume is sufficient to stimulate the growth of mouse PCa revealing the existence of a gut microbiome-cancer crosstalk. Analysis of gut microbial-related pathways in mice with aggressive PCa identifies three enzymes responsible for the metabolism of long-chain fatty acids (LCFA). Supplementation with LCFA omega-3 MAG-EPA is sufficient to reduce PCa growth in mice and cancer up-grading in pre-prostatectomy PCa patients correlating with a reduction of gut Ruminococcaceae in both and fecal butyrate levels in PCa patients. This suggests that the beneficial effect of omega-3 rich diet is mediated in part by modulating the crosstalk between gut microbes and their metabolites in men with PCa.

Embodying a self-avatar with a larger leg: its impacts on motor control and dynamic stability.

Several studies have shown that users of immersive virtual reality can feel high levels of embodiment in self-avatars that have different morphological proportions than those of their actual bodies. Deformed and unrealistic morphological modifications are accepted by embodied users, underlying the adaptability of one's mental map of their body (body schema) in response to incoming sensory feedback. Before initiating a motor action, the brain uses the body schema to plan and sequence the necessary movements. Therefore, embodiment in a self-avatar with a different morphology, such as one with deformed proportions, could lead to changes in motor planning and execution. In this study, we aimed to measure the effects on movement planning and execution of embodying a self-avatar with an enlarged lower leg on one side. Thirty participants embodied an avatar without any deformations, and with an enlarged dominant or non-dominant leg, in randomized order. Two different levels of embodiment were induced, using synchronous or asynchronous visuotactile stimuli. In each condition, participants performed a gait initiation task. Their center of mass and center of pressure were measured, and the margin of stability (MoS) was computed from these values. Their perceived level of embodiment was also measured, using a validated questionnaire. Results show no significant changes on the biomechenical variables related to dynamic stability. Embodiment scores decreased with asynchronous stimuli, without impacting the measures related to stability. The body schema may not have been impacted by the larger virtual leg. However, deforming the self-avatar's morphology could have important implications when addressing individuals with impaired physical mobility by subtly influencing action execution during a rehabilitation protocol.

Exploring the effects of 3D-360°VR and 2D viewing modes on gaze behavior, head excursion, and workload during a boxing specific anticipation task.

Introduction: Recent evidence has started to demonstrate that 360°VR, a type of VR that immerses a user within a 360° video, has advantages over two-dimensional (2D) video displays in the context of perceptual-cognitive evaluation and training. However, there is currently a lack of empirical evidence to explain how perceptual-cognitive strategies differ between these two paradigms when performing sports-related tasks. Thus, the objective of this study was to examine and compare the impact of different viewing conditions (e.g., 3D-360°VR and 2D video displays), on gaze behavior and head excursions in a boxing-specific anticipatory task. A secondary objective was to assess the workload associated with each viewing mode, including the level of presence experienced. Thirdly, an exploratory analysis was conducted to evaluate any potential sex differences. Methods: Thirty-two novice participants (16 females) were recruited for this study. A total of 24 single-punch sequences were randomly presented using a standalone VR headset (Pico Neo 3 Pro Eye), with two different viewing modes: 3D-360°VR and 2D. Participants were instructed to respond to the punches with appropriate motor actions, aiming to avoid punches. Gaze behavior was recorded using a Tobii eyetracker embedded in the VR headset. Workload and presence were measured with the SIM-TLX questionnaire. Fixation duration, number of fixations, saccades, search rate and head excursions (roll, pitch, yaw) were analyzed using linear mixed models. Results: The results revealed significant shorter fixation durations and more head excursions (roll, pitch) in 3D-360°VR, compared to the 2D viewing mode (ps < 0.05). The sense of presence was found to be much higher in the 3D-360°VR viewing mode (p < 0.05). No sex differences were observed. These results demonstrate that 360°VR elicited shorter fixation durations but mostly greater head excursions and immersion compared to a 2D projection in the context of a boxing-specific task. Discussion: These findings contribute to the understanding of previous evidence supporting the possible advantages of using 360°VR over 2D for perceptual-cognitive evaluation and training purposes. Further validation studies that compare behaviors and performance in 360°VR with those in the real-world will be needed.

A framework for equitable virtual rehabilitation in the metaverse era: challenges and opportunities.

Introduction: Metaverse technology is spurring a transformation in healthcare and has the potential to cause a disruptive shift in rehabilitation interventions. The technology will surely be a promising field offering new resources to improve clinical outcomes, compliance, sustainability, and patients' interest in rehabilitation. Despite the growing interest in technologies for rehabilitation, various barriers to using digital services may continue to perpetuate a digital divide. This article proposes a framework with five domains and elements to consider when designing and implementing Metaverse-based rehabilitation services to reduce potential inequalities and provide best patient care. Methods: The framework was developed in two phases and was informed by previous frameworks in digital health, the Metaverse, and health equity. The main elements were extracted and synthesized via consultation with an interdisciplinary team, including a knowledge user. Results: The proposed framework discusses equity issues relevant to assessing progress in moving toward and implementing the Metaverse in rehabilitation services. The five domains of the framework were identified as equity, health services integration, interoperability, global governance, and humanization. Discussion: This article is a call for all rehabilitation professionals, along with other important stakeholders, to engage in developing an equitable, decentralized, and sustainable Metaverse service and not just be a spectator as it develops. Challenges and opportunities and their implications for future directions are highlighted.

CdGAP is a talin-binding protein and a target of TGF-ß signaling that promotes HER2-positive breast cancer growth and metastasis.

Epithelial-to-mesenchymal transition (EMT) plays a crucial role in metastasis, which is the leading cause of death in breast cancer patients. Here, we show that Cdc42 GTPase-activating protein (CdGAP) promotes tumor formation and metastasis to lungs in the HER2-positive (HER2+) murine breast cancer model. CdGAP facilitates intravasation, extravasation, and growth at metastatic sites. CdGAP depletion in HER2+ murine primary tumors mediates crosstalk with a Dlc1-RhoA pathway and is associated with a transforming growth factor ß (TGF-ß)-induced EMT transcriptional signature. CdGAP is positively regulated by TGF-ß signaling during EMT and interacts with the adaptor talin to modulate focal adhesion dynamics and integrin activation. Moreover, HER2+ breast cancer patients with high CdGAP mRNA expression combined with a high TGF-ß-EMT signature are more likely to present lymph node invasion. Our results suggest CdGAP as a candidate therapeutic target for HER2+ metastatic breast cancer by inhibiting TGF-ß and integrin/talin signaling pathways.

Thermoneutrality and severe malaria: investigating the effect of warmer environmental temperatures on the inflammatory response and disease progression.

Introduction: Most studies using murine disease models are conducted at housing temperatures (20 - 22°C) that are sub-optimal (ST) for mice, eliciting changes in metabolism and response to disease. Experiments performed at a thermoneutral temperature (TT; 28 - 31°C) have revealed an altered immune response to pathogens and experimental treatments in murine disease model that have implications for their translation to clinical research. How such conditions affect the inflammatory response to infection with Plasmodium berghei ANKA (PbA) and disease progression is unknown. We hypothesized that changes in environmental temperature modulate immune cells and modify host response to malaria disease. To test this hypothesis, we conducted experiments to determine: (1) the inflammatory response to malarial agents injection in a peritonitis model and (2) disease progression in PbA-infected mice at TT compared to ST. Methods: In one study, acclimatized mice were injected intraperitoneally with native hemozoin (nHZ) or Leishmania at TT (28 - 31°C) or ST, and immune cells, cytokine, and extracellular vesicle (EV) profiles were determined from the peritoneal cavity (PEC) fluid. In another study, PbA-infected mice were monitored until end-point (i.e. experimental malaria score ≥4). Results: We found that Leishmania injection resulted in decreased cell recruitment and higher phagocytosis of nHZ in mice housed at TT. We found 398 upregulated and 293 downregulated proinflammatory genes in mice injected with nHZ, at both temperatures. We report the presence of host-derived EVs never reported before in a murine parasitic murine model at both temperatures. We observed metabolic changes in mice housed at TT, but these did not result to noticeable changes in disease progression compared to ST. Discussion: To our knowledge, these experiments are the first to investigate the effect of thermoneutrality on a malaria murine model. We found important metabolic difference in mice housed at TT. Our results offer insights on how thermoneutrality might impact a severe malaria murine model and directions for more targeted investigations.

SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation.

SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice. Mechanistic studies on DEN-induced genotoxic response revealed that SOCS1-deficient hepatocytes upregulate SOCS3 expression, SOCS3 promotes p53 activation, and Cdkn1a induction that were abolished by deleting either Socs3 or Tp53. Previous reports implicate CDKN1A in promoting oxidative stress response mediated by NRF2, which is required for DEN-induced hepatocarcinogenesis. We show increased induction of NRF2 and its target genes in SOCS1-deficient livers following DEN treatment that was abrogated by the deletion of either Cdkn1a or Socs3. Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the SOCS1-low/SOCS3-high subgroup displayed increased CDKN1A expression, enrichment of NRF2 transcriptional signature, faster disease progression, and poor prognosis. Overall, our findings show that SOCS1 deficiency in hepatocytes promotes compensatory SOCS3 expression, p53 activation, CDKN1A induction, and NRF2 activation, which can facilitate cellular adaptation to oxidative stress and promote neoplastic growth. Thus, the NRF2 pathway represents a potential therapeutic target in SOCS1-low/SOCS3-high HCC cases.

Comparison of sensitivity to taste and astringency stimuli among vegans and omnivores.

Taste perception plays a crucial role in determining food choices. It has been described in literature a relationship between diet composition and taste perception. Nowadays, with the rising concern in climate change and animal welfare, the number of people following a vegan diet is increasing to become a real trend. Research about differences in taste perception between vegan and omnivore is lacking. The aim of the study was to compare detection threshold for bitter, sour, umami and astringency stimuli (quinine monohydrochloride dihydrate, citric acid anhydrous, monosodium glutamate and tannic acid, respectively) participants following a vegan diet (n=24) and participants following an omnivore diet (n=30). Participants reported their consumption frequency for main food categories. The mean detection thresholds between the two groups narrowly missed significance with p-values of 0.07, 0.08, 0.06, for bitter, umami and astringency perception, respectively. No differences were found for sour taste (p-value=0.33). Further research is required to validate such findings and to understand the origin of the relationship between diet style and taste sensitivity.

To bind or not to bind: Cistromic reprogramming in prostate cancer.

The term "cistrome" refers to the genome-wide location of regulatory elements associated with transcription factor binding-sites. The cistrome of key regulatory factors in prostate cancer etiology are substantially reprogrammed and altered during prostatic transformation and disease progression. For instance, the cistrome of the androgen receptor (AR), a ligand-inducible transcription factor central in normal prostate epithelium biology, is directly impacted and substantially reprogrammed during malignant transformation. Accumulating evidence demonstrates that additional transcription factors that are frequently mutated, or aberrantly expressed in prostate cancer, such as the pioneer transcription factors Forkhead Box A1 (FOXA1), the homeobox protein HOXB13, and the GATA binding protein 2 (GATA2), and the ETS-related gene (ERG), and the MYC proto-oncogene, contribute to the reprogramming of the AR cistrome. In addition, recent findings have highlighted key roles for the SWI/SNF complex and the chromatin-modifying helicase CHD1 in remodeling the epigenome and altering the AR cistrome during disease progression. In this review, we will cover the role of cistromic reprogramming in prostate cancer initiation and progression. Specifically, we will discuss the impact of key prostate cancer regulators, as well as the role of epigenetic and chromatin regulators in relation to the AR cistrome and the transformation of normal prostate epithelium. Given the importance of chromatin-transcription factor dynamics in normal cellular differentiation and cancer, an in-depth assessment of the factors involved in producing these altered cistromes is of great relevance and provides insight into new therapeutic strategies for prostate cancer.

Comparison of RATA, CATA, sorting and Napping® as rapid alternatives to sensory profiling in a food industry environment.

Today, there is a need to accelerate new product development to deliver faster innovations which are expected by consumers. This requires identifying rapid descriptive methodologies requiring less training than conventional sensory profiling (SP) still providing good quality data allowing to identify food sensory drivers of consumer liking. A set of nine samples covering a large sensory space has been designed systematically combining at three different ratio three commercial almond, rice, and oat-based milks. Ten expert panellists familiar with sensory profiling and naïve with the plant-based milk category performed sorting, Napping®, CATA, RATA tasks and then SP. Overall liking of each sample was rated by 80 plant-based milk consumers. Among the four alternative methodologies, RATA provided both an overall product configuration and description the closest to SP (RV = 0.93) and allowed to identify the sensory drivers of plant-based milk acceptance similarly to SP. CATA is relevant to build a product landscape and to highlight product clusters with major sensory differences whereas Sorting and Napping® are alternatives to CATA, as product mappings were close, when no previous glossary or knowledge exits on product attributes.

The Extracellular Matrix Stiffening: A Trigger of Prostate Cancer Progression and Castration Resistance?

Despite advancements made in diagnosis and treatment, prostate cancer remains the second most diagnosed cancer among men worldwide in 2020, and the first in North America and Europe. Patients with localized disease usually respond well to first-line treatments, however, up to 30% develop castration-resistant prostate cancer (CRPC), which is often metastatic, making this stage of the disease incurable and ultimately fatal. Over the last years, interest has grown into the extracellular matrix (ECM) stiffening as an important mediator of diseases, including cancers. While this process is increasingly well-characterized in breast cancer, a similar in-depth look at ECM stiffening remains lacking for prostate cancer. In this review, we scrutinize the current state of literature regarding ECM stiffening in prostate cancer and its potential association with disease progression and castration resistance.

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets.

c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

Response to supraphysiological testosterone is predicted by a distinct androgen receptor cistrome.

The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression. However, as with any therapy, not all patients show a therapeutic benefit, and responses differ widely in magnitude and duration. In this study, we evaluated whether differences in the AR cistrome before treatment can distinguish between SPT-responding (R) and -nonresponding (NR) tumors. We provide the first preclinical evidence to our knowledge that SPT-R tumors exhibit a distinct AR cistrome when compared with SPT-NR tumors, indicating a differential biological role of the AR. We applied an integrated analysis of ChIP-Seq and RNA-Seq to the pretreatment tumors and identified an SPT-R signature that distinguishes R and NR tumors. Because transcriptomes of SPT-treated clinical specimens are not available, we interrogated available castration-resistant PC (CRPC) transcriptomes and showed that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT. These findings provide an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.

Protein tyrosine phosphatase 1B regulates miR-208b-argonaute 2 association and thyroid hormone responsiveness in cardiac hypertrophy.

Increased production of reactive oxygen species plays an essential role in the pathogenesis of several diseases, including cardiac hypertrophy. In our search to identify redox-sensitive targets that contribute to redox signaling, we found that protein tyrosine phosphatase 1B (PTP1B) was reversibly oxidized and inactivated in hearts undergoing hypertrophy. Cardiomyocyte-specific deletion of PTP1B in mice (PTP1B cKO mice) caused a hypertrophic phenotype that was exacerbated by pressure overload. Furthermore, we showed that argonaute 2 (AGO2), a key component of the RNA-induced silencing complex, was a substrate of PTP1B in cardiomyocytes and in the heart. Our results revealed that phosphorylation at Tyr393 and inactivation of AGO2 in PTP1B cKO mice prevented miR-208b-mediated repression of thyroid hormone receptor-associated protein 1 (THRAP1; also known as MED13) and contributed to thyroid hormone-mediated cardiac hypertrophy. In support of this conclusion, inhibiting the synthesis of triiodothyronine (T3) with propylthiouracil rescued pressure overload-induced hypertrophy and improved myocardial contractility and systolic function in PTP1B cKO mice. Together, our data illustrate that PTP1B activity is cardioprotective and that redox signaling is linked to thyroid hormone responsiveness and microRNA-mediated gene silencing in pathological hypertrophy.

The Challenge of Measuring Sweet Taste in Food Ingredients and Products for Regulatory Compliance: A Scientific Opinion.

The Codex Alimentarius Commission, a central part of the joint Food and Agricultural Organization/World Health Organizations Food Standards Program, adopts internationally recognized standards, guidelines, and code of practices that help ensure safety, quality, and fairness of food trade globally. Although Codex standards are not regulations per se, regulatory authorities around the world may benchmark against these standards or introduce them into regulations within their countries. Recently, the Codex Committee on Nutrition and Foods for Special Dietary Uses (CCNFSDU) initiated a draft revision to the Codex standard for follow-up formula (FUF), a drink/product (with added nutrients) for young children, to include requirements for limiting or measuring the amount of sweet taste contributed by carbohydrates in a product. Stakeholders from multiple food and beverage manufacturers expressed concern about the subjectivity of sweetness and challenges with objective measurement for verifying regulatory compliance. It is a requirement that Codex standards include a reference to a suitable method of analysis for verifying compliance with the standard. In response, AOAC INTERNATIONAL formed the Ad Hoc Expert Panel on Sweetness in November 2020 to review human perception of sweet taste, assess the landscape of internationally recognized analytical and sensory methods for measuring sweet taste in food ingredients and products, deliver recommendations to Codex regarding verification of sweet taste requirements for FUF, and develop a scientific opinion on measuring sweet taste in food and beverage products beyond FUF. Findings showed an abundance of official analytical methods for determining quantities of carbohydrates and other sweet-tasting molecules in food products and beverages, but no analytical methods capable of determining sweet taste. Furthermore, sweet taste can be determined by standard sensory analysis methods. However, it is impossible to define a sensory intensity reference value for sweetness, making them unfit to verify regulatory compliance for the purpose of international food trade. Based on these findings and recommendations, the Codex Committee on Methods of Analysis and Sampling agreed during its 41st session in May 2021 to inform CCNFSDU that there are no known validated methods to measure sweetness of carbohydrate sources; therefore, no way to determine compliance for such a requirement for FUF.

CdGAP promotes prostate cancer metastasis by regulating epithelial-to-mesenchymal transition, cell cycle progression, and apoptosis.

High mortality of prostate cancer patients is primarily due to metastasis. Understanding the mechanisms controlling metastatic processes remains essential to develop novel therapies designed to prevent the progression from localized disease to metastasis. CdGAP plays important roles in the control of cell adhesion, migration, and proliferation, which are central to cancer progression. Here we show that elevated CdGAP expression is associated with early biochemical recurrence and bone metastasis in prostate cancer patients. Knockdown of CdGAP in metastatic castration-resistant prostate cancer (CRPC) PC-3 and 22Rv1 cells reduces cell motility, invasion, and proliferation while inducing apoptosis in CdGAP-depleted PC-3 cells. Conversely, overexpression of CdGAP in DU-145, 22Rv1, and LNCaP cells increases cell migration and invasion. Using global gene expression approaches, we found that CdGAP regulates the expression of genes involved in epithelial-to-mesenchymal transition, apoptosis and cell cycle progression. Subcutaneous injection of CdGAP-depleted PC-3 cells into mice shows a delayed tumor initiation and attenuated tumor growth. Orthotopic injection of CdGAP-depleted PC-3 cells reduces distant metastasic burden. Collectively, these findings support a pro-oncogenic role of CdGAP in prostate tumorigenesis and unveil CdGAP as a potential biomarker and target for prostate cancer treatments.

EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer.

Prostate cancers are considered to be immunologically 'cold' tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs. In the present study, we demonstrate that EZH2 inhibition in prostate cancer models activates a double-stranded RNA-STING-ISG stress response upregulating genes involved in antigen presentation, Th1 chemokine signaling and interferon response, including programmed cell death protein 1 (PD-L1) that is dependent on STING activation. EZH2 inhibition substantially increased intratumoral trafficking of activated CD8+ T cells and increased M1 tumor-associated macrophages, overall reversing resistance to PD-1 CPI. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. These data suggest EZH2 inhibition as a therapeutic direction to enhance prostate cancer response to PD-1 CPI.

A multi-modal modified feedback self-paced BCI to control the gait of an avatar.

Brain-computer interfaces (BCIs) have been used to control the gait of a virtual self-avatar with a proposed application in the field of gait rehabilitation. Some limitations of existing systems are: (a) some systems use mental imagery (MI) of movements other than gait; (b) most systems allow the user to take single steps or to walk but do not allow both; (c) most function in a single BCI mode (cue-paced or self-paced).Objective. The objective of this study was to develop a high performance multi-modal BCI to control single steps and forward walking of an immersive virtual reality avatar.Approach. This system used MI of these actions, in cue-paced and self-paced modes. Twenty healthy participants participated in this study, which was comprised of four sessions across four different days. They were cued to imagine a single step forward with their right or left foot, or to imagine walking forward. They were instructed to reach a target by using the MI of multiple steps (self-paced switch-control mode) or by maintaining MI of forward walking (continuous-control mode). The movement of the avatar was controlled by two calibrated regularized linear discriminate analysis classifiers that used theµpower spectral density over the foot area of the motor cortex as a feature. The classifiers were retrained after every session. For a subset of the trials, positive modified feedback (MDF) was presented to half of the participants, where the avatar moved correctly regardless of the classification of the participants' MI. The performance of the BCI was computed on each day, using different control modes.Main results. All participants were able to operate the BCI. Their average offline performance, after retraining the classifiers was 86.0 ± 6.1%, showing that the recalibration of the classifiers enhanced the offline performance of the BCI (p< 0.01). The average online performance was 85.9 ± 8.4% showing that MDF enhanced BCI performance (p= 0.001). The average performance was 83% at self-paced switch control and 92% at continuous control mode.Significance. This study reports on a first BCI to use motor imagery of the lower limbs in order to control the gait of an avatar with different control modes and different control commands (single steps or forward walking). BCI performance is increased in a novel way by combining three different performance enhancement techniques, resulting in a single high performance and multi-modal BCI system. This study also showed that the improvements due to the effects of MDF lasted for more than one session.

Diet-Dependent Metabolic Regulation of DNA Double-Strand Break Repair in Cancer: More Choices on the Menu.

Despite several epidemiologic and preclinical studies supporting the role of diet in cancer progression, the complexity of the diet-cancer link makes it challenging to deconvolute the underlying mechanisms, which remain scantly elucidated. This review focuses on genomic instability as one of the cancer hallmarks affected by diet-dependent metabolic alterations. We discuss how altered dietary intake of metabolites of the one-carbon metabolism, including methionine, folate, and vitamins B and C, can impact the methylation processes and thereby tumorigenesis. We present the concept that the protumorigenic effect of certain diets, such as the Western diet, is in part due to a diet-induced erosion of the DNA repair capacity caused by altered epigenetic and epitranscriptomic landscapes, while the protective effect of other dietary patterns, such as the Mediterranean diet, can be partly explained by their ability to sustain a proficient DNA repair. In particular, considering that diet-dependent alterations of the one-carbon metabolism can impact the rate of methylation processes, changes in dietary patterns can affect the activity of writers and erasers of histone and RNA methyl marks and consequently impair their role in ensuring a proficient DNA damage repair.