Therapeutic Context Research Articles

Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer

No consensus strategies exist for prognosticating metastatic castration-resistant prostate cancer (mCRPC). Circulating tumor DNA fraction (ctDNA%) is increasingly reported by commercial and laboratory tests but its utility for risk stratification is unclear. Here, we intersect ctDNA%, treatment outcomes, and clinical characteristics across 738 plasma samples from 491 male mCRPC patients from two randomized multicentre phase II trials and a prospective province-wide blood biobanking program. ctDNA% correlates with serum and radiographic metrics of disease burden and is highest in patients with liver metastases. ctDNA% strongly predicts overall survival, progression-free survival, and treatment response independent of therapeutic context and outperformed established prognostic clinical factors. Recognizing that ctDNA-based biomarker genotyping is limited by low ctDNA% in some patients, we leverage the relationship between clinical prognostic factors and ctDNA% to develop a clinically-interpretable machine-learning tool that predicts whether a patient has sufficient ctDNA% for informative ctDNA genotyping (available online: https://www.ctDNA.org). Our results affirm ctDNA% as an actionable tool for patient risk stratification and provide a practical framework for optimized biomarker testing.

Radiogenomics in Oncology

The emergence of artificial intelligence in the digital era has brought about a significant transformation in the field of clinical decision support systems. The advent of technological advancements has led to the development of novel data-driven analytical algorithms, hence greatly augmenting human capacity to process information. The field of cancer radiogenomics presents a promising area within the realm of precision medicine. The objective of our research is to enhance our understanding of the genetic factors that contribute to the formation of tumors. This will be achieved by integrating extensive radiomics features extracted from medical imaging, genetic data obtained from clinical-epidemiological sources, and insights derived from high-throughput sequencing using mathematical modelling techniques. The aim of integrating radiomics and genomes is to gain a deeper understanding of the complex mechanisms behind cancer growth. The primary aim is to develop novel, empirically supported methodologies for the identification, prediction, and individualized therapeutic strategies for cancer, utilizing the acquired understanding. This comprehensive review aims to provide an overview of the existing body of research on the applications of radiogenomics, with a specific focus on solid malignancies. Additionally, we will examine the barriers that are now preventing the widespread integration of radiomics into therapeutic contexts.

To the screen, and beyond

ABSTRACT Digital technology has a ubiquitous presence in psychotherapy. While we recognize its immediate impact on our work, we are less attuned to its symbolic—yet highly consequential—implications for our field, much less its penetrating grip on the human psyche. The eight papers to follow offer us a beginning blueprint that invites us to revisit and re-calibrate our conception of psychotherapy in the digital age. They identify limitations and potential benefits of relating through the screen across multiple theoretical, clinical and training contexts, including a commentary on AI and the future of our field. Rather than shrinking ourselves to adjust to the screen’s limits, we need to expand our understanding of its impact both inside and outside of the therapeutic context.

Engineered RNA‐Binding Proteins: Studying and Controlling RNA Regulation

AbstractThe complexity of eukaryotic organisms is intricately tied to transcriptome‐level processes, notably alternative splicing and the precise modulation of gene expression through a sophisticated interplay involving RNA‐binding protein (RBP) networks and their RNA targets. Recent advances in our understanding of the molecular pathways responsible for this control have paved the way for the development of tools capable of steering and managing RNA regulation and gene expression. The fusion between a rapidly developing understanding of endogenous RNA regulation and the burgeoning capabilities of CRISPR‐Cas and other programmable RBP platforms has given rise to an exciting frontier in engineered RNA regulators. This review offers an overview of the existing toolkit for constructing synthetic RNA regulators using programmable RBPs and effector domains, capable of altering RNA sequence composition or fate, and explores their diverse applications in both basic research and therapeutic contexts.

Interoceptive experiences and ecological care: an embodied approach within therapeutical realms.

The conventional dichotomy between human health and disease has historically been approached through reductionist models that emphasize the exclusive causal relevance of physiological and pathological processes. Consequently, self-awareness and affective dimensions, integral to a phenomenological perspective, are often relegated to secondary traits, affording little consideration for the causal role of embodied living organization. Our interest lies in exploring the potential relevance of the phenomenology of embodied self-awareness in relation to interoceptive processes within therapeutic settings. As we illustrate, when the unfolding processes of interoceptive awareness and its affective capacity take precedence, the agent assumes an active, rather than passive, role in their own experience of health or illness. Departing from an enactive, phenomenological, and ecological standpoint, we propose a distinctive perspective on interoceptive processes, relying on an affective conceptualization of a spectrum of experiences of bodily being-in-the-world. Our primary argument posits that considering interoceptive processes from an embodied and ecological viewpoint of the self, interacting with the material and social environment, enables an approach to the gradient of affective experiences of embodied self-awareness-where pleasure or suffering is perceived and felt-in a naturalized, non-reductive, and relational manner. We discern two ways in which interoceptive processes interrelate with the experience of embodied self-awareness: sensitivity (self-affective) and affective-laden perception. Drawing on this distinction, we provide a nuanced description of these experiences within communities of cis-women, exemplified through the contexts of menstruation and endometriosis. This exploration seeks to enhance our understanding of the phenomenology of embodied, ecological, and affective self-experience from within diverse and situated bodies. The goal is to contribute to their autonomy and ability to adapt and self-regulate within therapeutic contexts.

Neuropsychological Insights into Coping Strategies: Integrating Theory and Practice in Clinical and Therapeutic Contexts

The primary focus of this review is to rigorously explore the application and significance of coping strategies within the domains of clinical psychology and neuropsychology. These consist of a variety of techniques, behaviors, and cognitive interventions, and their critical role in reinforcing resilience and facilitating adaptive responses to stressors has been highlighted. This study explores the complex neuropsychological links between the brain’s stress pathways and the use of coping mechanisms. The neural aspects of stress, and how they can be influenced by adaptive strategies, are detailed, illustrating the profound impact that these coping mechanisms have at a neurobiological level. Delving into the neuropsychological underpinnings, this review will shed light on how stress response pathways in the brain interact with, and can be modulated by, various coping strategies. These mechanisms are particularly salient when addressing the multifaceted challenges that are faced by individuals with neuropsychological or mental health issues. While these strategies span a broad spectrum, from introspection and cognitive reframing to behavioral activation and social support seeking, their integration and application remain diverse within clinical contexts. This review endeavors to elucidate the theoretical underpinnings of these strategies, their empirical support, and their practical implications within therapeutic interventions. Furthermore, the intricate interplay between individualized coping techniques and structured therapeutic methodologies will be examined, emphasizing the potential for a holistic treatment paradigm, thereby enhancing therapeutic outcomes and fostering individual resilience.

Cymraeg yn y Gweithle? An exploration into the proficiency and development of the Welsh language in psychology, counselling, and arts therapy services

The Welsh language has garnered increasing recognition and importance in Welsh healthcare. This study uses a mixed methods design to understand the use and development of the Welsh language within therapeutic services. 113 staff members from the psychology, counselling, and arts therapies service in Aneurin Bevan University Health Board completed a survey, exploring participants’ proficiency and confidence using the Welsh language, and their perspectives of the Welsh language within their respective services. Preliminary findings displayed a range of Welsh language proficiencies, from fluency to non-proficiency. Participants reported a lack of confidence in utilising the language, and resources, in their work. Qualitative findings further explicate the need to encourage development of proficiency by providing time for learning work-related skills and networking with other Welsh speakers. The findings illustrate a need to recognise language diversity and to understand the needs and development of multilingual practice within the therapeutic context.

Attitudes of patients and mental health professionals towards hypothetical use of serious games in psychotherapy.

The present study sought to identify the attitudes of psychotherapists and patients towards the hypothetical use of serious games in psychotherapy in the South African context. Online surveys assessed acceptance, experience, and requirements for the utilisation of serious games in therapeutic contexts. Clients utilising mental health services (n = 209) and psychotherapists delivering mental health services (n = 156) in South Africa completed the online survey. Knowledge about serious games is limited with only 15% of clients and 16% of therapists reporting knowledge of the existence and application of serious games. Use of serious games is even more infrequent with only 1% of therapists and 6% of clients currently using serious games as an intervention. Despite this, our findings highlight an apparent demand for their use, with 71% of therapists indicating that serious games would be a suitable adjunct treatment modality for their patients. Our results show a general openness toward the use of serious games in psychotherapy. The use of serious games as an e-mental health treatment modality is conceivable for both patients and therapists, particularly as a complementary strategy to traditional face-to-face psychotherapy.

Depression in the Paediatric Population: Current Therapeutic Context and Challenges to Innovation

Major depression, as a clinical condition associated with the highest rate of disability worldwide, presents very particular contours when it affects the pediatric population. The biochemical and pathophysiological changes associated with depression are naturally influenced by socioeconomic aspects and family dynamics, which contributes to great heterogeneity and variability in the symptoms expressed by children and adolescents. The COVID-19 pandemic, following the implementation of the necessary measures to mitigate the virus infection, has worsened mental illness in the general population, including the pediatric population, significantly contributing to an increase in cases of anxiety, depression and even of post-traumatic stress. This review aims to systematize the pathophysiological aspects of depression that manifests early in life, as well as its current therapeutic context, shedding some light on pharmacogenetics and the way in which multimodal drugs are designed to be used in the pediatric population. A search was conducted in the PubMed and Google Scholar databases, and only articles written in English and Portuguese published in journals indexed to the Web of Science were included in this review, as well as current guidelines for pharmacological prescription in pediatric depression. The results made it possible to compile current data on the efficacy and safety of medications used to treat this clinical situation and discuss the current paradigm of mental health in pediatrics.

The dopamine receptor D1 inhibitor, SKF83566, suppresses GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interactions.

Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context. GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo. Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, inhibited the growth of orthotopic GSC (BG5) derived xenografts in nude mice. DRD1 contributes to GBM invasion and progression by regulating c-Myc entry into the nucleus that affects the transcription of the UHRF1 gene. SKF83566 inhibits the transmembrane protein DRD1, and as such represents a candidate small therapeutic molecule for GBMs.

Immunomodulatory activities and biomedical applications of melittin and its recent advances.

Melittin (MLT), a peptide containing 26 amino acids, is a key constituent of bee venom. It comprises ∼40%-60% of the venom's dry weight and is the main pricing index for bee venom, being the causative factor of pain. The unique properties of MLT extracted from bee venom have made it a very valuable active ingredient in the pharmaceutical industry as this cationic and amphipathic peptide has propitious effects on human health in diverse biological processes. It has the ability to strongly impact the membranes of cells and display hemolytic activity with anticancer characteristics. However, the clinical application of MLT has been limited by its severe hemolytic activity, which poses a challenge for therapeutic use. By employing more efficient mechanisms, such as modifying the MLT sequence, genetic engineering, and nano-delivery systems, it is anticipated that the limitations posed by MLT can be overcome, thereby enabling its wider application in therapeutic contexts. This review has outlined recent advancements in MLT's nano-delivery systems and genetically engineered cells expressing MLT and provided an overview of where the MLTMLT's platforms are and where they will go in the future with the challenges ahead. The focus is on exploring how these approaches can overcome the limitations associated with MLT's hemolytic activity and improve its selectivity and efficacy in targeting cancer cells. These advancements hold promise for the creation of innovative and enhanced therapeutic approaches based on MLT for the treatment of cancer.

The augmentation of cytotoxic immune cell functionality through physical exertion bolsters the potency of chemotherapy in models of mammary carcinoma.

Mammary carcinoma, a pervasive and potentially lethal affliction, is conjectured to be profoundly influenced by physical exercise, both in prophylaxis and therapeutic contexts. This study endeavors to explore the repercussions of exercise training on the progression of mammary carcinoma, particularly the mechanisms by which the amalgamation of an exercise regimen and doxorubicin induces tumor cell apoptosis. Female BALB/c mice were categorized into four distinct groups: A sedentary group (SED), an exercise group (Ex), a doxorubicin group (Dox, 5 mg/kg), and a combined treatment group (Dox + Ex). The exercise training lasted for 21 days and included aerobic rotarod exercise and resistance training. The impact of exercise training on tumor growth, immune cell proportions, inflammatory factor levels, and cell apoptosis pathway was assessed. Exercise training significantly curtailed tumor growth in a mouse model of breast cancer. Both the Ex and Dox groups exhibited significant reductions in tumor volume and weight (p < 0.01) in comparison to the SED group, while the Dox + Ex group had a significantly lower tumor volume and weight than the Dox group (p < 0.01). Exercise training also significantly increased the proportion of NK and T cells in various parts of the body and tumor tissue, while decreasing tumor blood vessels density. Exercise training also increased IL-6 and IL-15 levels in the blood and altered the expression of apoptosis-related proteins in tumor tissue, with the combined treatment group showing even more significant changes. Physical training improves the effectiveness of doxorubicin in treating breast cancer by activating cytotoxic immune cells, releasing tumor suppressor factors, and initiating mt-apoptosis, all while mitigating the adverse effects of chemotherapy.

Varying Syntax to Enhance Verb-Focused Intervention for 30-Month-Olds With Language Delay: A Concurrent Multiple Baseline Design.

The purpose of this study is to determine if 2.5-year-olds with language delay would learn verbs (spill) when presented with varying syntactic structure ("The woman is spilling the milk"/"The milk is spilling"; milk = patient or theme) in a therapeutic context. Children with language delay have proportionally small inventories of verbs, which limits expressive language development. Children who have typical language development learn verbs more robustly when presented with alternating arguments than with a single argument structure. Three toddlers with expressive language delay (29-30 months of age) participated in a verb-focused treatment study using a concurrent multiple baseline design. Participants were shown action videos accompanied by sentences with varied argument structure for each target verb. To assess learning pre- and posttreatment, participants were asked to demonstrate actions corresponding to each verb. Visual inspection and tau analyses reveal significant posttreatment gains of target verbs taught with varying argument structures. Our results indicate that learning verbs with high variability of argument roles may facilitate a strong link between lexical representations of verbs and their syntactic structures. Using argument structure variability to teach verbs as an intervention strategy has great potential and should be tested further in larger group studies.

Carboplatin and Etoposide for the Treatment of Metastatic Prostate Cancer with or without Neuroendocrine Features: A French Single-Center Experience.

Chemotherapy using carboplatin and etoposide (CE) is frequently pragmatically proposed to treat metastatic prostate cancer (mPC), both primary small-cell neuroendocrine (PSC-NE) carcinoma and adenocarcinoma with or without neuroendocrine (NE) marker elevation. However, the real benefit of CE is poorly reported in the recent therapeutic context. We retrospectively analyzed the efficacy and tolerance of CE chemotherapy in these three different groups of mPC patients. Efficacy endpoints included radiological response, progression-free survival (PFS), and overall survival (OS), as well as PSA response and PFS2/PFS1 ratio in patients with adenocarcinoma. Sixty-nine patients were included in this single-center study (N = 18 with PSC-NE carcinoma and 51 with adenocarcinoma with (N = 18) or without (N = 33) NE marker elevation). Patients with adenocarcinoma were highly pretreated with next-generation hormonal agents (NHAs) and taxanes. In patients with adenocarcinoma, a PSA response ≥50% was observed in six patients (15.8%), four of whom had NE marker elevation. The radiological response was higher in PSC-NE and tended to be higher in adenocarcinoma when NE marker elevation was present. Comparing patients with adenocarcinoma with vs. without NE marker elevation, the median PFS was 3.7 and 2.1 months and the median OS was 7.7 and 4.7 months, respectively. Overall, 62.3% of patients experienced grade 3-4 adverse events (mainly hematological), and three treatment-related deaths were recorded. Reports of the clinical results of CE suggest that we should not mix PSC-NE and castration-resistant adenocarcinoma of the prostate. In patients with heavily pretreated adenocarcinoma, the benefit/risk ratio of CE chemotherapy seems unfavorable due to poor response and high toxicity.

A novel scenario in the therapeutic management of anemia of chronic kidney disease: placement and use of roxadustat.

Anemia is a frequent and early chronic kidney disease (CKD) complication. Its management is currently based on oral or intravenous iron supplements, erythropoiesis-stimulating agents, and red blood cell transfusions, when the benefits of transfusion outweigh the risks. Anemia in CKD patients is underdiagnosed and undertreated. Current standard of care is associated with challenges and therefore new treatment approacheshave been sought. Hypoxia-inducible factor-prolyl-hydroxylase enzyme inhibitors are a new class of orally administered drugs used to treat anemia associated with CKD. Small-molecule hypoxia-inducible factor-prolyl-hydroxylase inhibitors have a novel mechanism of action that activates the hypoxia-inducible factor (oxygen-sensing) pathway resulting in a coordinated erythropoietic response, leading to increased endogenous erythropoietin production, improved iron absorption and transport, and reduced hepcidin. Roxadustat is the first hypoxia-inducible factor-prolyl-hydroxylase inhibitor approved by the European Medicines Agency (EMA) and reimbursed in Italy by the Italian Medicines Agency (AIFA) for the treatment of adult patients with symptomatic CKD-related anemia. This authorization was based on the outcome of a globally-conducted phase 3 clinical trial program comprising eight pivotal multicenter randomized studies. In the absence of up-to-date guidelines, we performed a critical appraisal of the placement and use of roxadustat in this therapeutic context.

Clinical Informed Consent and ABA.

The online version contains supplementary material available at 10.1007/s40617-023-00902-0.

Fabric Pressure Sensors for Fine-Grained Interaction Detection in Plush Toys

Recent advances in fabric-based sensors have made it possible to densely instrument plush toys without altering their aesthetic or tactile appeal, unlike traditional sensors whose rigid components can negatively impact the interactive experience. This innovation opens a new realm of interaction possibilities, allowing for the detection of nuanced gestures and movements that are crucial for understanding behavior, enhancing engagement, and potentially monitoring cognitive functions in therapeutic contexts.

The development of the Epistemic Trust Rating System (ETRS)

Objective The present study introduces and validates the Epistemic Trust Rating System (ETRS), an observer-based measure designed to assess epistemic trust (ET) within psychotherapy. ET in psychotherapy has gained much theoretical attention as a critical component in the therapeutic context, given its inherent link to social communication. However, its empirical validation remains pending, largely due to the absence of a refined instrument to gauge ET levels within the therapy environment. Therefore, this study aimed to translate ET’s theoretical construct into tangible markers within the therapeutic context. Method One hundred eighteen patients enrolled in a randomized controlled trial received psychodynamic psychotherapy for depression. Incorporating top-down theoretical considerations with bottom-up empirical observations yielded an overall ETRS score accompanied by three distinct sub-scales, each assessing a singular ET element: one gauges the patient’s propensity to share; another measures the degree to which “we-mode” moments are achieved within the session; and the third evaluates the patient’s receptiveness to learning. Results The findings demonstrate the psychometric robustness of the ETRS, with good internal consistency, interrater reliability (ICC(1,8) = .86-.90), and convergent (r = .23-.29) and discriminant validity (r = -.10). Conclusion The current study highlights the ETRS as a promising tool bridging theory and empirical exploration, enhancing our understanding of epistemic trust in psychotherapy.

The use of Body-Mind Centering® to support training in Michael Chekhov’s acting technique

This article discusses the confluence of Body-Mind Centering (BMC)® practices with elements of Michael Chekhov’s technique as foundations for an integrated psychophysical approach to acting that does not build divisions between the actor’s body, psyche, and mind. For Chekhov, actors embody their characters from creative work, driven by embodied imagination and awareness of sensory perception. BMC® proposes ‘embodiment’, which is seen as an awareness process, at the cellular level, which occurs through the participant’s experience itself, not through intellectual understanding. Linking sensory perception to imagination the author emphasizes the respect for the singularity in both approaches: for BMC® any self-perception of the body is valued and for Chekhov, actor’s creative individuality must be respected. The author has investigated, in research-led workshops, experiences of the actor’s living anatomy from body systems and patterns as new grounds for Michael Chekhov’s acting technique. This work has explored a relationships between specific imaginary centres to correspondent organs and tissues of the body and particular movement qualities to specific body systems. The practice research revealed that BMC® broadens the perception of internal physical aspects, as a mental state, which supports the development of the skills sought by Chekhov for what he called ‘inspired acting’. Furthermore, the systematization achieved in this research can be applied to sectors beyond the theatre, resonating with Fleming and Cornford et al.’s argument for a use of Chekhov Technique in applied, community and therapeutic contexts (2020).

Vitamin C, doxycycline, and azithromycin (VDA) targeted changes in cellular senescence-related genes in human adipose-derived mesenchymal stem cells.

Adipose-derived Mesenchymal stem cells (ASCs) have garnered attention for their regenerative potential; therefore, their cellular senescence-related gene expression remains crucial in therapeutic contexts. Nowadays, combination therapies have shown promising results in reducing senescent cells. This study investigated the effects of vitamin C, doxycycline, and azithromycin co-treatment on the key cellular senescence-associated genes in ASCs. Human ASCs were cultured and treated for 24 hr with vitamin C, doxycycline, azithromycin, and a combination of three drugs. Total RNAs were extracted, and the expression of p21, p16, Nanog, Oct4, and Sox2 genes was assessed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Additionally, cell cycle alterations were analyzed via flow cytometry after treatment with these compounds. Notably, vitamin C treatment resulted in a significant down-regulation of p21 gene expression (P<0.01), implicating the potential role of vitamin C in promoting cell cycle progression. Doxycycline treatment led to a significant up-regulation of p21 and p16 gene expression (P<0.05), as it has previously been shown to induce cell cycle arrest. Similarly, azithromycin treatment predominantly increased p21 expression (P<0.05). Besides, cell cycle analysis revealed that each compound had changed the distribution of cells across different phases of the cell cycle. The combined use of all three drugs yielded intricate interactions, suggesting a complex yet promising approach to future research. According to our findings, the major difference in the combination drug-treated group (VDA) can be explained by the neutralizing effect of these three components in the environment.