Advances in immune checkpoint inhibitor combination strategies for microsatellite stable colorectal cancer

Colorectal cancer; Microsatellite stable; Tyrosine kinase inhibitorsCáncer colorrectal; Microsatélite estable; Inhibidores de la tirosina cinasaCàncer colorectal; Microsatèl·lit estable; Inhibidors de la tirosina cinasaImmune checkpoint inhibitors have reshaped the prognostic of several tumor types, including metastatic colorectal tumors with microsatellite instability (MSI). However, 90-95% of metastatic colorectal tumors are microsatellite stable (MSS) in which immunotherapy has failed to demonstrate meaningful clinical results. MSS colorectal tumors are considered immune-cold tumors. Several factors have been proposed to account for this lack of response to immune checkpoint blockade including low levels of tumor infiltrating lymphocytes, low tumor mutational burden, a high rate of WNT/β-catenin pathway mutations, and liver metastases which have been associated with immunosuppression. However, studies with novel combinations based on immune checkpoint inhibitors are showing promising activity in MSS colorectal cancer. Here, we review the underlying biological facts that preclude immunotherapy activity, and detail the different immune checkpoint inhibitor combinations evaluated, along with novel immune-based therapies, to overcome innate mechanisms of resistance in MSS colorectal cancer

CDX-2 expression correlates with clinical outcomes in MSI-H metastatic colorectal cancer patients receiving immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic colorectal cancer (mCRC) with mismatch-repair deficiency or high microsatellite instability (dMMR-MSI-H). Unfortunately, a patient's subgroup did not benefit from immunotherapy. Caudal-related homeobox transcription factor 2 (CDX-2) would seem to influence immunotherapy's sensitivity, promoting the chemokine (C-X-C motif) ligand 14 (CXCL14) expression. Therefore, we investigated CDX-2 role as a prognostic-predictive marker in patients with mCRC MSI-H. We retrospectively collected data from 14 MSI-H mCRC patients treated with ICIs between 2019 and 2021. The primary endpoint was the 12-month progression-free-survival (PFS) rate. The secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and disease control rate (DCR). The PFS rate at 12 months was 81% in CDX-2 positive patients vs 0% in CDX-2 negative patients (p = 0.0011). The median PFS was not reached (NR) in the CDX-2 positive group versus 2.07 months (95%CI 2.07-10.8) in CDX-2 negative patients (p = 0.0011). Median OS was NR in CDX-2-positive patients versus 2.17 months (95% Confidence Interval [CI] 2.17-18.7) in CDX2-negative patients (p = 0.026). All CDX-2-positive patients achieved a disease response, one of them a complete response. Among CDX-2-negative patients, one achieved stable disease, while the other progressed rapidly (ORR: 100% vs 0%, p = 0.0005; DCR: 100% vs 50%, p = 0.02). Twelve patients received 1st-line pembrolizumab (11 CDX-2 positive and 1 CDX-2 negative) not reaching median PFS, while two patients (1 CDX-2 positive and 1 CDX-2 negative) received 3rd-line pembrolizumab reaching a median PFS of 10.8 months (95% CI, 10.8-12.1; p = 0.036). Although our study reports results on a small population, the prognostic role of CDX-2 in CRC seems confirmed and could drive a promising predictive role in defining the population more sensitive to immunotherapy treatment. Modulating the CDX-2/CXCL14 axis in CDX-2-negative patients could help overcome primary resistance to immunotherapy

Effect of saliva moistening on shear bond strength of self ligating orthodontic brackets

The purpose of the present study was to compare Shear Bond Strength (SBS) and bond failure site of conventional and Self-Ligating (SL) orthodontic brackets, bonded on dry and saliva contaminated enamel. Approach: One conventional and three different types of self ligating stainless steel brackets were bonded onto 160 bovine permanent mandibular incisors, divided randomly into 8 groups, using Transbond XT adhesive system. For each type of bracket, 20 samples were bonded on dry enamel and 20 after saliva contamination. After 24 h all specimens were tested for SBS using an instron universal testing machine and Adhesive Remnant Index (ARI) were evaluated. Results: Saliva contamination significantly lowered SBS of conventional brackets. For self-ligating brackets no significant strength reduction was recorded. Conclusion: All the groups showed clinically adequate mean shear bond strengths. ARI scores in contaminated groups resulted lower than in dry groups

L\u2019alterazione del processo emozionale nella Malattia di Parkinson: feedback facciale e risposta autonomica

La malattia di Parkinson (PD) presenta tipicamente un\u2019alterazione nell\u2019elaborazione e nel riconoscimento delle emozioni, ma non \ue8 ancora noto se perdano del tutto tale capacit\ue0 o se la compromissione riguardi la percezione dell\u2019emozione in s\ue9, la regolazione fisiologica in risposta a stimoli emotivi o la decodifica delle emozioni altrui. Questo studio si propone di indagare i meccanismi di riconoscimento emotivo in tali pazienti, utilizzando alcune misure: la valutazione esplicita delle emozioni (Self-Assessment Manikin, SAM) e la reattivit\ue0 implicita (conduttanza cutanea, SCR; la risposta elettromiografica, EMG). Sono stati selezionati 20 pazienti sulla base di una valutazione neuropsicologica, abbinati per et\ue0 e scolarit\ue0 a 34 volontari sani. Ai pazienti era chiesto di osservare e valutare immagini emotivamente salienti, scelte dall\u2019International Affective Picture System (IAPS) durante la rilevazione autonomica con biofeedback. L\u2019integrazione di dati comportamentali e autonomici ha consentito un confronto diretto tra la valutazione soggettiva delle emozioni (valenza e arousal) e la reazione fisiologica corrispondente. In secondo luogo, la misura elettromiografica (zigomatico e corrugatore) ha evidenziato il ruolo che la modulazione centrale e periferica ha sulla risposta emotiva. I pazienti in risposta a stimoli negativi ad alto arousal hanno mostrato valori SCR inferiori rispetto ai soggetti sani confermati anche a livello elettromiografico: ad una ridotta mimica corrugatoria \ue8 collegata una risposta periferica ridotta. I pazienti PD sembrano quindi non rispondere adeguatamente alle categorie emozionali che vengono considerate salienti in condizioni normali; il fenomeno si osserva soprattutto per una categoria emotiva specifica, per la quale ad una capacit\ue0 preservata di riconoscimento delle emozioni non corrisponde un\u2019adeguata risposta autonomica

Effetto della neuromodulazione corticale (tDCS) nell'healthy ageing. Correlati EEG e comportamentali

Nella cornice teorica dell\u2019active and healthy ageing, l\u2019invecchiamento fisiologico \ue8 visto come un processo dinamico che pu\uf2 offrire opportunit\ue0 per il mantenimento e il potenziamento delle capacit\ue0 cognitive e affettivo-sociali. In quest\u2019ottica, gli interventi di empowerment mediante neuromodulazione si offrono come potenziali strumenti per il contenimento del fisiologico declino cognitivo e delle sue derive patologiche. Sulla base delle evidenze relative al coinvolgimento primario nel processo di invecchiamento delle strutture neurali prefrontali e delle funzioni esecutive da esse mediate, \ue8 stato predisposto un protocollo di potenziamento mediato da stimolazione cerebrale non-invasiva (tDCS). Il confronto integrato di misure di outcome psicometriche ed elettrofisiologiche (potenziali evento- relati, ERP) tra gruppo sperimentale e gruppo di controllo ha evidenziato profili di miglioramento a favore del primo, con un incremento dei punteggi ottenuti ai test sulle funzioni esecutive e delle risposte elettrofisiologiche associate a processi di orientamento attentivo (N200). Tali effetti sono stati parzialmente mantenuti anche alla rilevazione di follow-up, suggerendo interessanti implicazioni delle tecniche di neuromodulazione in percorsi preventivi o di intervento precoce

Effetti a breve e a lungo termine della neuromodulazione corticale (tDCS) e del training cognitivo nell\u2019healthy ageing. Correlati EEG e comportamentali

Nella cornice teorica dell\u2019active and healthy ageing, interventi di empowerment cognitivo ed elettrofisiologico si offrono come potenziali strumenti per il contenimento del fisiologico declino cognitivo e delle sue derive patologiche. Sulla base delle evidenze relative al coinvolgimento primario delle strutture prefrontali e delle funzioni esecutive da esse mediate nell\u2019invecchiamento, sono stati progettati e indagati due protocolli di potenziamento mediato, rispettivamente, da training cognitivo computerizzato e da stimolazione cerebrale non-invasiva (tDCS). Al fine di valutarne anche gli effetti di neuroplasticit\ue0, l\u2019indagine ha integrato classiche misure psicometriche con indicatori elettrofisiologici (potenziali evento-relati, ERP) di outcome. Un gruppo di controllo e due gruppi sperimentali composti da anziani senza deficit cognitivi acuti o cronici hanno preso parte allo studio e si sono quindi sottoposti a una valutazione elettrofisiologica e neuropsicologica standardizzata all\u2019inizio e alla fine della fase di intervento, e a distanza di sei mesi. Entrambi i protocolli sperimentali prevedevano un percorso di otto settimane con tre sessioni la settimana. Le analisi, realizzate controllando l\u2019effetto delle differenze individuali, hanno evidenziato profili di miglioramento differenti a favore dei gruppi sperimentali, con un incremento dei punteggi ottenuti ai test standardizzati sulle funzioni esecutive e delle risposte elettrofisiologiche associate a processi di orientamento attentivo (N200). Tali effetti sono stati parzialmente mantenuti anche alla rilevazione di follow-up, suggerendo interessanti implicazioni delle tecniche di neuromodulazione in percorsi preventivi o di intervento precoce. In aggiunta, le evidenze suggeriscono come l\u2019integrazione di diverse misure (EEG e dati comportamentali) sia cruciale per un adeguato confronto tra protocolli differenti e per la valutazione di diversi profili di risposta a diversi trattamenti di potenziamento

Facial feedback effect explains the autonomic impairment in PD for emotional recognition

Parkinson\u2019s Disease (PD) is a degenerative neurological disorder of the central nervous system with a strong impact on both social and emotional level. Parkinson patients typically present with emotional processing impairment in emotional experience and emotion recognition. However, it is not yet known whether these patients have lost the capability to feel the emotions intrinsically, to modulate to emotional experience associating subjective response with physiological modulations, or to decipher emotions in others. The present research aims at investigating the contribution of central, peripheral and facial feedback measures in PD patients when they processed emotional cues using a multilevel approach, comparting selfreport (appraisal), autonomic (Skin Conductance Response, SCR) and motor electromyographic (EMG zygomaticus and corrugators facial muscles) measures. The integration of these measures allowed firstly a direct comparison between the explicit appraisal of emotions (with specific reference to the two parameters of valence and arousal) and the autonomic responsiveness to emotions. Secondly the role of EMG (zygomaticus and corrugators muscle) in determining the central and peripheral modulation was explored. Indeed the facial feedback model supposed that the autonomic facial response by facial muscles may affect both the emotional appraisal and the physiological modulation. 20 patients have been selected and 34 healthy volunteers (HC), matched for age and education. PD patients observed and evaluated affective pictures that were chosen from International Affective Picture System (IAPS). These pictures concerned four types of stimuli: 10 pleasant \u2013 low and high arousal; 10 unpleasant \u2013 low and high arousal, 5 neutral. PD patients seemed to not adequately answer to the emotional categories which were considered salient in standard conditions (HC). Indeed, there was an autonomic impairment for a category- specific emotion (negative and high arousal). Particularly, patients have revealed an inadequate sensibility (reduced SCR) only for negative emotional condition. In parallel EMG behavior was disrupted (reduced corrugators activity) in response to negative high arousal emotional cues. However, PD patients were able to correctly categorize the emotional cues based on their valence/arousal, probably due to a \u201cgap\u201d between this central process and the autonomic system activity. Then, the regression analysis pointed out the predictive role of the corrugators activity to explain the impaired autonomic response: a reduced corrugators mimic was linked to a reduced peripheral responsiveness toward the negative and high arousal emotional stimuli

From Investigation to Intervention. Biofeedback and Neurofeedback Biomarkers in Sport

Sport neuroscience, lying at the intersection of applied neuroscience and sport psychology, includes, among its hot topics, the cognitive and affective processes and mechanisms that accompany the athletic performance. This chapter focuses on present applications of psychophysiological and electrophysiological techniques, such as biofeedback and neurofeedback, to support or empower performance in sports. In particular, you will find an introduction to the mechanisms of action of most relevant techniques in the field, neural-bodily-behavioral modulations that are targeted by different intervention opportunities, and technical application notes. We will discuss the value of self-awareness and of the ability to properly recognize bodily feedbacks, especially when athletes have to face competition, and the relevance of robust self-regulation skills to achieve maximum performance. Further, we will report a critical comparison between the efficacy and strong/weak points of bio/neurofeedback techniques and more traditional mental training techniques within the field of sport science. Finally, we will present and discuss different protocols applied to specific sports, such as baseball, golf, soccer, and gymnastics

Long-term empowerment effect of executive functions by multisession neuromodulation in healthy aging: follow-up evidences

Non-Invasive Brain Stimulation (NIBS) techniques proved to be valuable tools in supporting cognitive empowerment in case of both neurodegenerative diseases and functional impairments due to cerebrovascular events. However, little research systematically explored their potential contribution to containment and prevention of physiological cognitive decline in healthy aging. Further, the majority of those studies actually focused on the effect of single stimulation sessions with limited investigation of their long-term maintenance. The present report extends previous finding concerning short-term empowerment effects of an integrated multi-session neuromodulation protocol on executive functioning by showing intervention-related long-term effects in a sample of healthy elderly people. In order to explore perceived sustainability and short/long-term intervention outcomes, we divided 23 participants into a control and an experimental group and asked them to complete a standardized neuropsychological and electrophysiological (i.e. recording of event-related potentials during an executive attention task) assessment at the beginning of the study (T0), at the end of the intervention period (T1) and after further six months (T2). The integrated intervention protocol lasted eight weeks and included three anodal transcranial Direct Current Stimulation (tDCS) sessions (15 minutes, 1.5 mA, right prefrontal placement with contralateral supraorbital cephalic reference) per week with twice-weekly executive functions tasks. Mixed effects models accounting for subjectrelated and time-related confound highlighted relevant performance increases in the experimental group with respect to the control one at the end of the intervention. In particular, we observed higher scores at standardized tests tapping on executive functions (abstract reasoning, cognitive flexibility and verbal generation) and enhanced automatic attention responses. Such improvements were partially maintained even at the follow-up. To sum up, the multisession neuromodulation protocol proved to be able to induce empowerment of specific cognitive abilities even in healthy aging, with interesting long-term effects. Our findings support the notion that integrated neuromodulation protocols may offer valuable intervention opportunities for cognitive decline prevention