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Purpose.To report on the case manager's activity in a hospital setting as a supporting professional for families that need to deal with different services and professionals to get answers on their health and psychosocial needs. Method.A qualitative analysis and interpretation based on the case manager observations and ICF checklist evaluation with medical and rehabilitation professionals were employed. Results.The case study presented aimed to show one of the most typical interventions of the case manager: the creation of a network around a person with complex and multifaceted needs, where this network does not exist. Case manager bridged the gap between health and social services, specifically organising home-based rehabilitation and helping to find appropriate assistive devices. Conclusions.This case study showed that the case manager's role is fundamental to support patients and their families in relating to the different services and professionals they need, and illustrated one of the most typical interventions of the case manager: the creation of a network around a person with complex and multifaceted needs, where this network does not exist. [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) remains a dire disease being the first cause of cancer death among both genders. Early-stage NSCLC often has better treatment outcomes despite it being a highly heterogeneous disease. So far, the neo-adjuvant chemotherapy strategies have led to a small benefit with an improvement of 5% in overall survival as an absolute benefit. Recently, the introduction of immune checkpoint inhibitors combined with chemotherapy has shown robust efficacy in terms of event-free survival and overall survival. Thus, these combinations are today considered a new standard of care in early-stage NSCLC. The application of these strategies to all-comer population lead to confounding definitive results regarding the efficacy and predictive biomarkers are urgently needed balancing the promise of healing than toxicities. At present, the clinical staging TNM system guides the clinical choice, however it is not entirely sufficient. Circulant tumoral DNA (ctDNA) emerged as a promising prognostic and predictive biomarker that may guide the future perioperative strategy and pave the way to personalized medicine also in this exciting field. This narrative review aims to put in the context the employment of ctDNA, give some perspective and suggestions weighing the pros and cons of this technique for our tomorrow clinical practice., Competing Interests: Declarations. Competing interest: The authors declare no competing interests., (© 2025. The Author(s).)

Psychedelics have emerged as promising therapeutics for several psychiatric disorders. Hypotheses around their mechanisms have revolved around their partial agonism at the serotonin 2 A receptor, leading to enhanced neuroplasticity and brain connectivity changes that underlie positive mindset shifts. However, these accounts fail to recognise that the gut microbiota, acting via the gut-brain axis, may also have a role in mediating the positive effects of psychedelics on behaviour. In this review, we present existing evidence that the composition of the gut microbiota may be responsive to psychedelic drugs, and in turn, that the effect of psychedelics could be modulated by microbial metabolism. We discuss various alternative mechanistic models and emphasize the importance of incorporating hypotheses that address the contributions of the microbiome in future research. Awareness of the microbial contribution to psychedelic action has the potential to significantly shape clinical practice, for example, by allowing personalised psychedelic therapies based on the heterogeneity of the gut microbiota., Competing Interests: Declaration of Competing Interest WAJ is a founder and shareholder of the University of British Columbia Start-up Mynd Life Sciences. All other authors declare no known competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Emerging cancers are sculpted by neo-Darwinian selection for superior growth and survival but minimal immunogenicity; consequently, metastatic cancers often evolve common genetic and epigenetic signatures to elude immune surveillance. Immune subversion by metastatic tumours can be achieved through several mechanisms; one of the most frequently observed involves the loss of expression or mutation of genes composing the MHC-I antigen presentation machinery (APM) that yields tumours invisible to Cytotoxic T lymphocytes, the key component of the adaptive cellular immune response. Fascinating ethnographic and experimental findings indicate that cannabinoids inhibit the growth and progression of several categories of cancer; however, the mechanisms underlying these observations remain clouded in uncertainty. Here, we screened a library of cannabinoid compounds and found molecular selectivity amongst specific cannabinoids, where related molecules such as Δ9-tetrahydrocannabinol, cannabidiol, and cannabigerol can reverse the metastatic immune escape phenotype in vitro by inducing MHC-I cell surface expression in a wide variety of metastatic tumours that subsequently sensitizing tumours to T lymphocyte recognition. Remarkably, H3K27Ac ChIPseq analysis established that cannabigerol and gamma interferon induce overlapping epigenetic signatures and key gene pathways in metastatic tumours related to cellular senescence, as well as APM genes involved in revealing metastatic tumours to the adaptive immune response. Overall, the data suggest that specific cannabinoids may have utility in cancer immunotherapy regimens by overcoming immune escape and augmenting cancer immune surveillance in metastatic disease. Finally, the fundamental discovery of the ability of cannabinoids to alter epigenetic programs may help elucidate many of the pleiotropic medicinal effects of cannabinoids on human physiology., Competing Interests: WAJ was the founder and held financial interest in the University of British Columbia start-up, Pascal Biosciences. NG, CW, PG, and LT were employees of and hold a financial interest in Pascal Biosciences. 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 Dada, Ellis, Wood, Nohara, Dreier, Garcia, Saranchova, Munro, Pfeifer, Eyford, Kari, Garrovillas, Caspani, Al Haddad, Gray, Morova, Lack, Andersen, Tjoelker and Jefferies.)

Decades of research have established the role of microbiota-brain communication in behaviour and brain function. Studies have shown that microbiota composition and diversity are influenced by a variety of factors including host genetics, diet, and other environmental exposures, with implications for the immunological and neurobiological development of the host organism. To further understand early-life interactions between environment, genetic factors, the microbiome and the central nervous system, we investigated the impact of postnatal stress in C57Bl/6 wild type and T-cell deficient mice on microbe-brain interactions and behaviour. Mice were exposed to immune challenge with lipopolysaccharide (LPS) at postnatal day (P) 3 and maternal separation at P9 (16 h overnight). Behavioural assessment of growth and development as well as behaviour (righting reflex, ultrasonic vocalizations in response to brief maternal separation, open field, sociability, and grooming) was conducted. Microbiota diversity and composition of fecal samples collected at P24 revealed reduced alpha diversity in T-cell-deficient mice as well as genotype- and stress-related taxa. Notably, integrated analyses of microbiota and behaviour in the context of immunocompromise revealed key behavioural related taxa that may be important to brain development. These findings are important to determining the influence of genetic and environmental factors on gut microbiota and advances our understanding microbiome-brain signaling pathways on neurodevelopment and behaviour.

Despite the progress in characterising the pharmacological profile of drugs of abuse, their precise biochemical impact remains unclear. The metabolome reflects the multifaceted biochemical processes occurring within a biological system. This includes those encoded in the genome but also those arising from environmental/exogenous exposures and interactions between the two. Using metabolomics, the biochemical derangements associated with substance abuse can be determined as the individual transitions from recreational drug to chronic use (dependence). By understanding the biomolecular perturbations along this time course and how they vary across individuals, metabolomics can elucidate biochemical mechanisms of the addiction cycle (dependence/withdrawal/relapse) and predict prognosis (recovery/relapse). In this review, we summarise human and animal metabolomic studies in the field of opioid and psychostimulant addiction. We highlight the importance of metabolomics as a powerful approach for biomarker discovery and its potential to guide personalised pharmacotherapeutic strategies for addiction targeted towards the individual's metabolome. LINKED ARTICLES: This article is part of a themed issue on Building Bridges in Neuropharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.8/issuetoc., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Cross-talk between the immune system and the brain is essential to neuronal development, neuronal excitability, neuroplasticity, and neurotransmission. Gut microbiota are essential to immune system development and immune function; hence, it is essential to consider more broadly the microbiota-immune-brain axis in neurodevelopment. The gut, brain, and microbial metabolomes obtained from C57Bl/6 and T-cell-deficient mice across four developmental timepoints (postnatal day 17, 24, 28, and 84) were studied by 1 H NMR spectroscopy. 16S rRNA gene sequencing was performed on cecal and fecal samples. In the absence of T-cells, the developmental trajectory of the gut microbiota and of the host's metabolic profile was altered. The novel insights from this work include (1) the requirement of functional T-cells for the normal trajectory of microbiotal development and the metabolic maturation of the supra-organism, (2) the potential role for Muribaculaceae taxa in modulating the cecal availability of metabolites previously implicated with a role in the gut-brain axis in T-cell deficient mice, and (3) the impact of T-cell-deficiency on central levels of neuroactive metabolites.

One of the biggest challenges in treating depression is the heterogeneous and qualitative nature of its clinical presentations. This highlights the need to find quantitative molecular markers to tailor existing treatment strategies to the individual's biological system. In this study, high-resolution metabolic phenotyping of urine and plasma samples from the CAN-BIND study collected before treatment with two common pharmacological strategies, escitalopram and aripiprazole, was performed. Here we show that a panel of LDL and HDL subfractions were negatively correlated with depression in males. For treatment response, lower baseline concentrations of apolipoprotein A1 and HDL were predictive of escitalopram response in males, while higher baseline concentrations of apolipoprotein A2, HDL and VLDL subfractions were predictive of aripiprazole response in females. These findings support the potential of metabolomics in precision medicine and the possibility of identifying personalized interventions for depression., (© 2021. The Author(s).)

The wealth of biotransformational capabilities encoded in the microbiome expose the host to an array of bioactive xenobiotic products. Several of these metabolites participate in the communication between the gastrointestinal tract and the central nervous system and have potential to modulate central physiological and pathological processes. This biochemical interplay can occur through various direct and indirect mechanisms. These include binding to host receptors in the brain, stimulation of the vagus nerve in the gut, alteration of central neurotransmission, and modulation of neuroinflammation. Here, the potential for short chain fatty acids, bile acids, neurotransmitters and other bioactive products of the microbiome to participate in the gut-brain axis will be reviewed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Gastrointestinal and central function are intrinsically connected by the gut microbiota, an ecosystem that has co-evolved with the host to expand its biotransformational capabilities and interact with host physiological processes by means of its metabolic products. Abnormalities in this microbiota-gut-brain axis have emerged as a key component in the pathophysiology of depression, leading to more research attempting to understand the neuroactive potential of the products of gut microbial metabolism. This review explores the potential for the gut microbiota to contribute to depression and focuses on the role that microbially-derived molecules - neurotransmitters, short-chain fatty acids, indoles, bile acids, choline metabolites, lactate and vitamins - play in the context of emotional behavior. The future of gut-brain axis research lies is moving away from association, towards the mechanisms underlying the relationship between the gut bacteria and depressive behavior. We propose that direct and indirect mechanisms exist through which gut microbial metabolites affect depressive behavior: these include (i) direct stimulation of central receptors, (ii) peripheral stimulation of neural, endocrine, and immune mediators, and (iii) epigenetic regulation of histone acetylation and DNA methylation. Elucidating these mechanisms is essential to expand our understanding of the etiology of depression, and to develop new strategies to harness the beneficial psychotropic effects of these molecules. Overall, the review highlights the potential for dietary interventions to represent such novel therapeutic strategies for major depressive disorder., Competing Interests: Conflict of interest: The authors declare no conflict of interest.

Background: Survivors of critical illness in childhood commonly display subsequent psychiatric symptoms including emotional and behavioural difficulties, and manifestations of post-traumatic stress disorder (PTSD). Anomalies in inflammatory profiles are an established finding in these childhood psychiatric conditions., Objective: This exploratory study aimed to investigate whether abnormal peripheral blood inflammatory markers measured during paediatric intensive care unit (PICU) admission were associated with psychiatric symptoms after discharge., Methods: We performed a prospective observational cohort study on 71 children with septic illness, meningoencephalitis and other critical disorders admitted to two PICUs between 2007 and 2010. 3-6 months following discharge, subjects were assessed for global psychiatric risk (ie, presence of emotional and behavioural difficulties on the parental Strengths and Difficulties Questionnaire (SDQ)), and for PTSD risk using the child-rated Impact of Events Scale (IES-8). Inflammatory and related biological markers were transcribed from PICU admission notes (white cell count, lymphocytes, neutrophils, C reactive protein (CRP), platelets, fibrinogen and lactate)., Findings: Global psychiatric risk at follow-up was associated with abnormal lymphocyte count during admission (χ 2 =6.757, p=0.014, n=48). In children with sepsis, partial correlation analyses controlling for age and gender highlighted associations between (i) SDQ scores and low lymphocyte count (r=-0.712; p=0.009, n=14), and (ii) IES-8 score and high CRP levels (r=0.823; p=0.006, n=11). These associations remained after correction for multiple comparisons., Conclusion: These results support the hypothesis that acute inflammation may play a role in determining the development of psychopathology following PICU admission., Clinical Implications: If the findings are replicated, they may help to better highlight which children are at risk of post-PICU psychopathology and appropriately target follow-up., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Background: Five percent to 20% of stage I endometrial cancer patients undergoing total abdominal hysterectomy and bilateral salpingo-oophorectomy develop vaginal and pelvic recurrences. Adjuvant radiotherapy can improve locoregional control but not survival. This randomized trial aimed to determine whether a modified radical (Piver-Rutledge class II) hysterectomy can improve survival and locoregional control compared to the standard extrafascial (Piver-Rutledge class I) hysterectomy., Methods: Eligible patients (n = 520) with stage I endometrial cancer were randomized to class I or class II hysterectomy. Primary endpoint was overall survival., Results: The median length of parametria and vagina removed were 15 and 5 vs. 20 mm and 15 mm for class I and class II hysterectomy, respectively (P > 0.001). Operating time and blood loss were statistically significantly higher for class II hysterectomy. At a median follow-up of 70 months, 51 patients had died. Five-year disease-free and overall survival were similar between arms (87.7 and 88.9% in the class I arm and 89.7 and 92.2% in the class II arm, respectively). The unadjusted hazard ratios for recurrence was 0.91 (95% confidence interval, 0.55-1.51, P = 0.72), and the hazard ratio for death was 0.77 (95% confidence interval, 0.44-1.33, P = 0.35)., Conclusions: Class II hysterectomy did not improve locoregional control and survival compared to class I hysterectomy, but when an adequate vaginal cuff transection is not feasible with class I hysterectomy, a modified radical hysterectomy allows to obtain an optimal vaginal and pelvic control of disease with a minimal increase in surgical morbidity.

Background: Ovarian carcinosarcoma (OCS) is a rare malignancy associated with a poor prognosis. Platinum, anthracyclines, and alkylating agents are the most effective antiblastic drugs for treatment of gynecologic epithelial and stromal tumors. The aim of this study was to determine response rate and overall survival (OS) of patients with OCS who were treated with a combination of these 3 drugs., Methods: Forty-one women with OCS who were referred to the Department of Gynecologic Oncology of San Gerardo Hospital in Monza and European Institute of Oncology in Milan, between January 1995, and December 2006, and treated with a combination regimen of cisplatin, adriamycin, and cyclophosphamide or a combination regimen containing of cisplatin, epirubicin, and ifosfamide plus granulocyte colony-stimulating factor were considered for this study., Results: Four women had OCS stage I; 7, stage II; 23, stage III; and 7, stage IV. Heterologous, homologous, and mixed stromal components were described in 17, 14, and 10 patients, respectively. Thirteen women were treated with a combination of cisplatin, adriamycin, and cyclophosphamide and 28 with a combination of cisplatin, epirubicin, and ifosfamide plus granulocyte colony-stimulating factor. Two women did not complete their treatment because of the rapid progression of their disease and severe toxicity. Among 22 women considered evaluable for response, 10 (46%) achieved a complete response and 3 (13%) achieved a partial response (global response rate, 59%). Overall progression-free survival was 11.8 months (range, 0.9-96 months) and 13.8 and 10.1 months in stage I-II and III-IV, respectively (P = 0.13). Median OS was 20 months (range, 1-123 months), not reached in stage I-II, and 19.7 months in stage III-IV (P = 0.07). No significant difference between homologous and heterologous sarcomatous components was observed (P = 0.95), whereas no significant trend of improved OS was noticed for stage IIIC-IV with optimal debulking surgery (n = 9), compared with suboptimal cytoreduction (n = 19; 32.6 vs 14.5 months, P = 0.14)., Conclusion: The combination of anthracycline, alkylating agent, and cisplatin showed a good response rate but also a high toxicity. The prognosis of OCS remains poor. Optimal cytoreduction may improve survival, but new anticancer drugs or more effective regimens are awaited.

Recent studies have shown that probiotics are beneficial in T-cell-mediated inflammatory diseases. The molecular mechanism by which probiotics work remains elusive, but accumulating evidence indicates that probiotics can modulate immune cell responses. Since T cells express receptors for bacterial products or components, we examined whether different strains of lactobacilli directly regulate the functions of human T cells. CD4(+) T cells were isolated from blood and intestinal lamina propria (LP) of normal individuals and patients with inflammatory bowel disease (IBD). Mononuclear cells were also isolated from Peyer's patches. Cells were activated with anti-CD3/CD2/CD28 in the presence or absence of Lactobacillus paracasei subsp. paracasei B21060, L. paracasei subsp. paracasei F19, or L. casei subsp. casei DG. Cell proliferation and death, Foxp3, intracellular pH, and cytokine production were evaluated by flow cytometry. We showed that L. paracasei subsp. paracasei B21060 but neither L. paracasei subsp. paracasei F19 nor L. casei subsp. casei DG inhibited blood CD4(+) T-cell growth. This effect was associated with no change in cell survival, expression of Foxp3, or production of gamma interferon, interleukin-4 (IL-4), IL-5, and IL-10. L. paracasei subsp. paracasei B21060-mediated blockade of CD4(+) T-cell proliferation required a viable bacterium and was associated with decreased MCT-1 expression and low intracellular pH. L. paracasei subsp. paracasei B21060 also inhibited the growth of Peyer's patch mononuclear cells, normal lymphocytes, and IBD CD4(+) LP lymphocytes without affecting cytokine production. The data show that L. paracasei subsp. paracasei B21060 blocks T-cell growth, thus suggesting a mechanism by which these probiotics could interfere with T-cell-driven immune responses.

The clinical treatment of malignant epithelial ovarian cancer limited to the gonad(s) involves many problems that have given rise to analyses in recent literature and to different approaches: i. intensive anatomo-radio-surgical staging, evaluation and clinical incidence of prognostic risk factors; ii. re-staging of patients after inadequate and incomplete surgery; iii. indications, role and topicality of second-look surgery; iv. conservative surgery in patients of a fertile age wishing to have children and retain activity of the gonads; v. laparoscopic surgery for treatment, staging, re-staging and surveillance; vi. the lymph node issue; vii. adjuvant therapy: indications, options, type of drugs, doses and length; viii. quality and frequency of surveillance; ix. malignant epithelial ovarian cancer limited to the gonads in pregnancy. The clinical handling of these tumours entails many complex problems causing emotional involvement since it is most frequent at a fertile age.

The loss of mismatch repair enzymes increases the mutation rate in microsatellites and coding regions of the genome and appears to be involved in drug resistance. The replication error (RER+) phenotype, associated with microsatellite instability, has been widely described for both familial and sporadic colon cancers and for gastric and endometrial tumors. For ovarian cancer, the incidence of RER+ cases among sporadic tumors is still uncertain. We analyzed epithelial ovarian tumors and ovarian carcinoma cell lines for microsatellite instability and for mutations in the coding regions of different genes, including the recently discovered human CHK-1 gene, which has an important role in controlling cell cycle progression and whose coding region contains a poly(A)9 tract. Microsatellite instability and frameshift mutations in coding regions of BAX, TGFbetaRII, IGFIIR, E2F-4, ICE, and CHK-1 genes were analyzed in ovarian cancer samples and cell lines by polymerase chain reaction (PCR). Approximately 26% of patients showed microsatellite instability in two or more loci. BAT-26 locus showed no alteration in primary tumors. We detected a BAX mutation in one tumor sample and a TGFbetaRII mutation in one cell line. Our findings confirm the presence of the RER+ phenotype in sporadic ovarian cancer. The low rate of mutation in genes previously reported to be altered in colon and gastric cancer suggests that other not yet identified genes might be altered and could play a role in tumor progression and response to treatment in RER+ ovarian tumors.

Interleukin 1 (IL-1) induces a series of metabolic and endocrine effects. Activation of the hypothalamus-pituitary-adrenal axis, inhibition of food and water intake, elevation of serum interleukin-6 (IL-6) concentration and hypoglycemia are some of the effects induced by IL-1. The purpose of this study was to compare the sensitivity of these effects following central and peripheral administration of IL-1 beta. Different doses of IL-1 beta (0.1-1000 ng/mouse) were centrally (ICV) or peripherally (IP) injected to male mice two hours prior to sacrifice. The ICV administration was more efficacious than the IP injection in elevating serum corticosterone and IL-6 concentrations, whereas no difference was evident in the IL-1 beta-induced hypoglycemia. Central IL-1 beta administration was also more potent than IP injection in inhibiting overnight food and water intake. A dose-dependent effect was evident in all these cases. In summary, our data compare effects elicited by central or peripheral administration of different doses of IL-1 beta. This comparison suggests that the IL-1 beta stimulation of serum corticosterone and IL-6 and inhibition of food and water intake are events more centrally mediated than the IL-1 beta-induced hypoglycemia.

Glucose-induced inactivation of the gluconeogenetic enzymes fructose-1,6-biphosphatase, cytoplasmic malate dehydrogenase and phosphoenolpyruvate carboxykinase was tested in yeast mutants defective in adenylate cyclase (cyr1 mutation) and in the cAMP-binding subunit of cAMP-dependent protein kinase (bcy 1 mutation). In the mutant AM7-11D (cyr1 mutation), glucose-induced cAMP overshoot was absent, and no significant inactivation of the gluconeogenetic enzymes was detected, thus supporting the role of cAMP in the process. Moreover, in the mutant AM9-8B (bcy1 mutation), no cAMP-dependent protein kinase activity was evidenced, and, in addition, a normal inactivation pattern was observed, thus indicating that other mechanisms evoked by glucose might be required in the process. In the double mutant AM7-11DR-4 (cyr1 bcy1 mutations), no inactivating effect was triggered by the sugar: this suggests that cAMP exerts some additional effect on the process, besides the activation of cAMP-dependent protein kinase. Furthermore, in AM7-11D, extracellular cAMP triggered about 50% of inactivation of fructose-1,6-bisphosphatase; this effect was largely reversed in acetate medium plus cycloheximide even after 150 min of incubation. However, an extensive and essentially irreversible inactivation was evidenced in the presence of glucose plus cAMP, whereas glucose alone was only slightly effective. Therefore, the reversible effect of cAMP, which probably corresponds to enzyme phosphorylation, seems to be required for the irreversible, probably proteolytic, glucose-stimulated inactivation of this enzyme. Cytoplasmic malate dehydrogenase and phosphoenolpyruvate carboxykinase in AM7-11D were also inactivated by cAMP, and much more by glucose plus cAMP, whereas glucose was practically ineffective. However, reversibility of the effect was not detected, and, in addition, no phosphorylation of phosphoenolpyruvate carboxykinase could be evidenced. Therefore, the sugar quite probably stimulates proteolysis of these enzymes, but the mechanism of cAMP in their degradation has still to be defined.