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The repurposing of previously clinically approved drugs as an alternative therapeutic approach to treating disease has gained significant attention in recent years. A multitude of studies have demonstrated various and successful therapeutic interventions with these drugs in a wide range of neoplastic diseases, including multiple myeloma, leukaemia, glioblastoma, and colon cancer. Drug repurposing has been widely encouraged due to the known efficacy, safety, and convenience of already established drugs, allowing the bypass of the long and difficult road of lead optimization and drug development. Repurposing drugs in cancer therapy is an exciting prospect due to the ability of these drugs to successfully target cancer-associated genes, often dysregulated in oncogenic signalling pathways, amongst which are the classical cancer signalling pathways; WNT (wingless-related integration type) and Hippo signalling. These pathways play a fundamental role in controlling organ size, tissue homeostasis, cell proliferation, and apoptosis, all hallmarks of cancer initiation and progression. Prolonged dysregulation of these pathways has been found to promote uncontrolled cellular growth and malignant transformation, contributing to carcinogenesis and ultimately leading to malignancy. However, the translation of cancer signalling pathways and potential targeted therapies in cancer treatment faces ongoing challenges due to the pleiotropic nature of cancer cells, contributing to resistance and an increased rate of incomplete remission in patients. This review provides analyses of a range of potential anti-cancer compounds in drug repurposing. It unravels the current understanding of the molecular rationale for repurposing these drugs and their potential for targeting key oncogenic signalling pathways.

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Determining peripheral modulation of the endocannabinoid system (ECS) may be important for differentiating individuals with schizophrenia. Such differentiation can also be extended to subgroups of individuals, those who use cannabis and antipsychotic medications, particularly those who are treatment resistant. Patients and controls were recruited from the outpatient clinic of the Psychosis Group of the University of São Paulo, Brazil. A final sample of 93 individuals was divided into 3 groups: patients with schizophrenia using clozapine (treatment-resistant) (n = 29), patients with schizophrenia using another antipsychotic (n = 31), and controls (n = 33). By measuring the proteins and metabolites involved in the ECS pathways in the peripheral blood, AEA (anandamide), 2-AG (2-arachidonoyl ethanolamine), and CB2 receptor (peripheral) were quantified. Individuals reporting lifetime cannabis use had lower 2-AG plasma levels (p = 0.011). Regarding the CB2 receptor, the values of patients with schizophrenia and controls were similar, but those of patients using antipsychotics other than clozapine differed (p = 0.022). In generalized linear models to control for confounders, the use of cannabis remained the only factor that significantly influenced 2-AG levels. The relationship for non-clozapine antipsychotics as the only factor related to CB2 changes was marginally significant. We found for the first time that cannabis use and non-clozapine antipsychotic medication are potentially involved in the modulation of the ECS, specifically influencing 2-AG endocannabinoid and CB2 receptor levels. More studies regarding the ECS are needed since it has been increasingly related to the physiopathology of schizophrenia.

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BACKGROUND: Cannabis use is associated with an increased risk of developing a psychotic disorder. However, in individuals with at-risk mental states for psychosis (ARMS) this association is not clear, as well as the impact of cannabis use on symptom severity. The objective of this study was to evaluate the association of cannabis use patterns and ARMS risk status, transition to psychotic and psychiatric disorders, and psychopathology. METHOD: A sample of 109 ARMS and 197 control individuals was drawn from the general population. Lifetime, maximum and current amount of cannabis use were assessed with the South Westminster modified questionnaire. Participants were followed-up for a mean of 2.5 years and reassessed for transition to any psychiatric disorder. RESULTS: There were no differences between ARMS and controls regarding lifetime use, current amount of use, or maximum amount of cannabis use. There were also no differences between those who transitioned to a psychiatric disorder and those who did not regarding cannabis use variables. In ARMS individuals, cannabis use was significantly related to disorganization symptoms. CONCLUSION: The results of this study suggest that cannabis plays a role in the psychopathology of ARMS individuals, leading to more severe symptomatology.

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BACKGROUND: Neurotrophins (NTs) and their precursors (pro-NTs) are polypeptides with important roles in neuronal development, differentiation, growth, survival and plasticity, as well as apoptosis and neuronal death. Imbalance in NT levels were observed in schizophrenia spectrum disorders, but evidence in ultra-high risk for psychosis (UHR) samples is scarce. METHODS: A naturalistic sample of 87 non-help-seeking UHR subjects and 55 healthy controls was drawn from the general population. Blood samples were collected and NT-3, NT-4/5, BDNF, pro-BDNF, NGF, pro-NGF were analyzed through enzyme linked immunosorbent assay (ELISA). Information on cannabis and tobacco use was also collected. Logistic regression models and path analysis were used to control for confounders (tobacco, age, cannabis use). RESULTS: NT-4/5 was significantly decreased, and pro-BDNF was significantly increased in UHR individuals compared to controls. Cannabis use and higher NGF levels were significantly related to transition to psychiatric disorders among UHR subjects. Increased pro-BDNF and decreased NT-4/5 influenced transition by the mediation of perceptual abnormalities. CONCLUSIONS: Our study shows for the first time that NTs are altered in UHR compared to healthy control individuals, and that they can be a predictor of transition to psychiatric illnesses in this population. Future studies should employ larger naturalistic samples to confirm the findings.

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AIMS: Our study aimed to develop a machine learning ensemble to distinguish "at-risk mental states for psychosis" (ARMS) subjects from control individuals from the general population based on facial data extracted from video-recordings. METHODS: 58 non-help-seeking medication-naïve ARMS and 70 healthy subjects were screened from a general population sample. At-risk status was assessed with the Structured Interview for Prodromal Syndromes (SIPS), and "Subject's Overview" section was filmed (5-10 min). Several features were extracted, e.g., eye and mouth aspect ratio, Euler angles, coordinates from 51 facial landmarks. This elicited 649 facial features, which were further selected using Gradient Boosting Machines (AdaBoost combined with Random Forests). Data was split in 70/30 for training, and Monte Carlo cross validation was used. RESULTS: Final model reached 83 % of mean F1-score, and balanced accuracy of 85 %. Mean area under the curve for the receiver operator curve classifier was 93 %. Convergent validity testing showed that two features included in the model were significantly correlated with Avolition (SIPS N2 item) and expression of emotion (SIPS N3 item). CONCLUSION: Our model capitalized on short video-recordings from individuals recruited from the general population, effectively distinguishing between ARMS and controls. Results are encouraging for large-screening purposes in low-resource settings.

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Anaplastic thyroid carcinoma (ATC) is a rare, but aggressive, carcinoma derived from follicular cells. While conventional treatments may improve patients' survival, the lethality remains high. Therefore, there is an urgent need for more effective ATC treatments. Cardiotonic steroids, such as ouabain, have been shown to have therapeutic potential in cancer treatment. Thus, we aimed to evaluate ouabain's effects in human anaplastic thyroid cells. For this, 8505C cells were cultured in the presence or absence of ouabain. Viability, cell death, cell cycle, colony formation and migratory ability were evaluated in ouabain-treated and control 8505C cells. The expression of differentiation and epithelial-to-mesenchymal transition (EMT) markers, as well as IL-6, TGFb1 and their respective receptors were also quantified in these same cells. Our results showed that ouabain in vitro decreased the number of viable 8505C cells, possibly due to an inhibition of proliferation. A reduction in migration was also observed in ouabain-treated 8505C cells. In contrast, decreased mRNA levels of PAX8 and TTF1 differentiation markers and increased levels of the N-cadherin EMT marker, as well as IL-6 and TGFb1, were found in ouabain-treated 8505C cells. In short, ouabain may have anti-proliferative and anti-migratory effect on 8505C cells, but maintains an aggressive and undifferentiated profile.

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Movement abnormalities are commonly observed in schizophrenia and at-risk mental states (ARMS) for psychosis. They are usually detected with clinical interviews, such that automated analysis would enhance assessment. Our aim was to use motion energy analysis (MEA) to assess movement during free-speech videos in ARMS and control individuals, and to investigate associations between movement metrics and negative and positive symptoms. Thirty-two medication-naïve ARMS and forty-six healthy control individuals were filmed during speech tasks. Footages were analyzed using MEA software, which assesses movement by differences in pixels frame-by-frame. Two regions of interest were defined-head and torso-and mean amplitude, frequency, and coefficient of variability of movements for them were obtained. These metrics were correlated with the Structured Interview for Prodromal Syndromes (SIPS) symptoms, and with the risk of conversion to psychosis-inferred with the SIPS risk calculator. ARMS individuals had significantly lower mean amplitude of head movement and higher coefficients of movement variability for both head and torso, compared to controls. Higher coefficient of variability was related to higher risk of conversion. Negative correlations were seen between frequency of movement and most SIPS negative symptoms. All positive symptoms were correlated with at least one movement variable. Movement abnormalities could be automatically detected in medication-naïve ARMS subjects by means of a motion energy analysis software. Significant associations of movement metrics with symptoms were found, supporting the importance of movement analysis in ARMS. This could be a potentially important tool for early diagnosis, intervention, and outcome prediction.

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ABSTRACT: Clinical high-risk (CHR) individuals belong to a heterogeneous group, of which only a few will cross the threshold for a clinical diagnosis. Cognitive disturbances are present in CHR subjects and may be indicative of transition. Our study aims to identify such deficits in a representative CHR for psychosis sample. Our sample comprised 92 CHR individuals and 54 controls from a representative cohort of the general population. They were followed up for a mean of 2.5 years, with 15 individuals converting to schizophrenia or other Diagnostic and Statistical Manual of Mental Disorders, 5th Edition diagnoses. Neurocognitive assessment was performed with the University of Pennsylvania Computerized Neuropsychological Testing, and CHR status was assessed with the Structured Interview for Prodromal Syndromes (SIPS). Baseline scores were entered in a latent profile analysis model. Our study brought forward a four-class model on cognitive performance. One class displayed better performance, whereas the other three performed worse, all compared with controls. The class with lower executive function also had the highest score on disorganized communication (SIPS P5 = 1.36, p < 0.05), although unrelated to conversion. Among the low performers, the class significantly related to conversion (p = 0.023) had the highest score in decreased expression of emotion (SIPS N3 = 0.85, p < 0.05). Our study brings new and relevant data on non-help-seeking CHR individuals and the relationship between cognitive patterns and conversion. We have highlighted a specific cognitive signature, associated with negative symptoms, which represents a stable trait with presumed lower conversion to a psychiatric illness.

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Ouabain is a steroid described as a compound extracted from plants that is capable of binding to Na+ , K+ -ATPase, inhibiting ion transport and triggering cell signaling pathways. Due to its positive ionotropic effect, ouabain was used for more than 200 years for the treatment of cardiac dysfunctions. Numerous antitumor effects of ouabain have been described so far; however, its role on thyroid cancer is still poorly understood. Therefore, the aim of the present work was to evaluate the effect of ouabain on the biology of human papillary thyroid cancer cells. For this, three human thyroid cell lines were used: NTHY-ori, a non-tumor lineage, BCPAP and TPC-1, both derived from papillary carcinomas. Cells were cultured in the presence or absence of ouabain. Subsequently, we evaluated its effects on the viability, cell death, cell cycle, and migratory ability of these cell lines. We also investigated the impact of ouabain in IL-6/IL-6R and epithelial to mesenchymal transition markers expression. Our results indicate that ouabain (10-7 M), decreased the number of NTHY-ori, TPC-1 and BCPAP viable cells and induced cell cycle arrest after in vitro culture, but did not appear to promote cell death. In TPC-1 cells ouabain also inhibited cell migration; increased IL-6/IL-6R expression and IL-6 secretion; and diminished vimentin and SNAIL-1 expression. Collectively, our results indicate that ouabain has an antitumoral role on human papillary thyroid carcinomas in vitro. Even though additional studies are necessary, our work contributes to the discussion of the possibility of new clinical trials of ouabain.

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BACKGROUND: Vaginal stenosis (VS) is a common side effect of pelvic radiotherapy for gynecological cancer in women. It has a high incidence variability, likely due to unstandardized and subjective assessment methods. Furthermore, even though the worldwide standard treatment for VS is vaginal dilation, low compliance rates have been noted. AIM: To evaluate the parameters used to diagnose VS and to assess whether the lack of an objective measure of VS hampers vaginal dilator use. METHODS: A systematic review in accordance with the PRISMA reporting guidelines was conducted. PubMed, EMBASE, and Web of Science databases were searched. Randomized trials and prospective, retrospective, and cross-sectional studies published from January 2011 to February 2020 were included. OUTCOMES: The main outcome of this study was a review of the published literature on assessment methods for VS and compliance to vaginal dilator use. RESULTS: Of the 28 articles obtained, only 7 used objective methods to measure the vaginal volume. 3 studies have demonstrated patient's concern with VS development and showed a high compliance to dilator use, whereas others reported several barriers to dilator use. CLINICAL IMPLICATIONS: Lack of an objective assessment method can be a predisposing factor for uncertain VS incidence rates and impair compliance to vaginal dilator therapy, leading to long-term VS and sexual dysfunction. STRENGTHS & LIMITATIONS: This is the first systematic review on the heterogeneity of VS evaluation methods and compliance to vaginal dilator use. All studies were comprehensively evaluated by 2 reviewers. The limitations included the heterogeneity of the study designs and the unstandardized criteria used to classify stenosis or to evaluate compliance to dilator use. Although 3 well-known databases were used, the inclusion of more data sources could have increased the number of publications included in this review. CONCLUSION: VS is frequently diagnosed using subjective parameters. Few unstandardized objective methods are used to evaluate this condition. Regarding compliance to vaginal dilator use, there was a high dropout rate during follow-up and no consensus on starting time or ideal usage. Haddad NC, Soares Brollo LC, Pinho Oliveira MA, et al. Diagnostic Methods for Vaginal Stenosis and Compliance to Vaginal Dilator Use: A Systematic Review. J Sex Med 2021;18:493-514.

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There are promising results in the use of platelet-rich plasma (PRP) for musculoskeletal tissue repair. However, the variability in the methodology for its obtaining may cause different and opposing findings in the literature. Particularly, the choice of the anticoagulant is the first definition to be made. In this work, blood was collected with sodium citrate (SC), ethylenediaminetetraacetic acid (EDTA), or anticoagulant citrate dextrose (ACD) solution A, as anticoagulants, prior to PRP obtaining. Hematological analysis and growth factors release quantification were performed, and the effects on mesenchymal stromal cell (MSC) culture, such as cytotoxicity and cell proliferation (evaluated by MTT method) and gene expression, were evaluated. The use of EDTA resulted in higher platelet yield in whole blood; however, it induced an increase in the mean platelet volume (MPV) following the blood centrifugation steps for PRP obtaining. The use of SC and ACD resulted in higher induction of MSC proliferation. On the other hand, PRP obtained in SC presented the higher platelet recovery after the blood first centrifugation step and a minimal change in MSC gene expression. Therefore, we suggest the use of SC as the anticoagulant for PRP obtaining.

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Complicações no membro superior encontram-se entre as principais repercussões após a cirurgia do câncer de mama e remoção dos linfonodos axilares, sendo a Síndrome da Rede Axilar (SRA) uma condição comumente observada no pós-operatorio imediato, e que consiste no surgimento de um cordoamento tenso e doloroso, oriundo da região axilar, que gera restrição de movimento no braço homolateral à cirurgia, e é decorrente do processo de cicatrização, que por sua vez é fundamental para o sucesso da cirurgia. A SRA pode causar incapacidade funcional no membro superior, especialmente por estar associada à restrição da amplitude de movimento do ombro e à dor, sendo o comprometimento da função do ombro mais um fator limitante nas atividades da vida diária (AVDs), de higiene pessoal, e na sua autonomia, o que repercute também no estado emocional da mulher. Apesar de ser descrita como uma síndrome autolimitada, com remissão espontânea em até 3 meses de seu surgimento, estudos mostram que, em alguns casos, ela pode estender-se além desse prazo, ou mesmo sofrer recidiva e piorar a incapacidade. Um agravante é o fato de ser uma questão subvalorizada na prática clínica, e por não haver orientação formal às pacientes sobre o risco de surgimento da síndrome, o tratamento costuma ser realizado tardiamente, o que pode prolongar o comprometimento funcional. A intervenção fisioterapêutica tem sido utilizada no pré e pós-operatório das cirurgias de mama para evitar as limitações físico-funcionais decorrentes da cirurgia, porém, o seu uso na SRA não está bem consolidada na literatura, bem como as estratégias educacionais sobre a síndrome ainda não fazem parte da rotina das orientações fisioterapêuticas pós-operatórias, de forma que as pacientes desconhecem os sinais, sintomas e características da SRA. Desta forma, os objetivos do presente trabalho foram: caracterizar o perfil sóciodemográfico e de saúde das mulheres submetidas ao tratamento cirúrgico para câncer de mama em um Hospital Universitário; relatar o efeito da intervenção fisioterapêutica precoce póscirúrgica para câncer de mama devido à SRA a partir do estudo de caso; elaborar um Plano de cuidados fisioterapêuticos de rotina no referido hospital e elaborar material educacional em forma de cartilha informativa para as pacientes em pós-cirúrgico de câncer de mama

Among the main repercussions after surgery for breast cancer and removal of axillary lymph nodes are complications in the arm. The healing process is critical to the success of the surgery, but may result in Axillary Web Syndrome (AWS) a commonly observed condition in the immediate post-operative, and that is the emergence of a tense and painful stranding, arising from the axillary region, generating restriction of movement in the ipsilateral arm surgery. AWS can cause functional impairment in the upper limb, especially to be associated with the restriction of shoulder range of motion and pain, and impairment of shoulder function more a limiting factor in activities of daily living (ADLs), personal hygiene, and their autonomy, which also affects the emotional state of women. Despite being described as a self-limited syndrome with spontaneous remission within 3 months of its inception, studies show that in some cases it may extend beyond that period, or even suffer relapse and worsen disability. An aggravating factor is the fact that it is a matter undervalued in clinical practice, and there is no formal guidance to patients about the risk of developing the syndrome, treatment is usually performed later, which can prolong the functional impairment. The physical therapy intervention has been used before and after surgery of breast surgery to avoid the physical and functional limitations resulting from surgery, however, its use in AWS is not well established in the literature, as well as educational strategies on the syndrome yet not part of the routine of postoperative physical therapy guidelines, so that the patients are unaware of the signs, symptoms and characteristics of AWS. Thus, the objectives of this study were to characterize the socio-demographic and health profiles of women undergoing surgery for breast cancer in a university hospital; report the effect of postoperative early physical therapy intervention for breast cancer due to AWS; develop a routine physical therapy care plan in that hospital and prepare an information booklet to patients in post-surgical breast cancer

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Pituitary adenomas comprise approximately 10-15% of intracranial tumors and result in morbidity associated with altered hormonal patterns, therapy and compression of adjacent sella turcica structures. The use of functional foods containing carotenoids contributes to reduce the risk of chronic diseases such as cancer and vascular disorders. In this study, we evaluated the influence of different concentrations of beta-carotene and lycopene on cell viability, colony formation, cell cycle, apoptosis, hormone secretion, intercellular communication and expression of connexin 43, Skp2 and p27(kip1) in ACTH-secreting pituitary adenoma cells, the AtT20 cells, incubated for 48 and 96 h with these carotenoids. We observed a decrease in cell viability caused by the lycopene and beta-carotene treatments; in these conditions, the clonogenic ability of the cells was also significantly decreased. Cell cycle analysis revealed that beta-carotene induced an increase of the cells in S and G2/M phases; furthermore, lycopene increased the proportion of these cells in G0/G1 while decreasing the S and G2/M phases. Also, carotenoids induced apoptosis after 96 h. Lycopene and beta-carotene decreased the secretion of ACTH in AtT20 cells in a dose-dependent manner. Carotenoids blocked the gap junction intercellular communication. In addition, the treatments increased the expression of phosphorylated connexin43. Finally, we also demonstrate decreased expression of S-phase kinase-associated protein 2 (Skp2) and increased expression of p27(kip1) in carotenoid-treated cells. These results show that lycopene and beta-carotene were able to negatively modulate events related to the malignant phenotype of AtT-20 cells, through a mechanism that could involve changes in the expression of connexin 43, Skp2 and p27(kip1); and suggest that these compounds might provide a novel pharmacological approach to the treatment of Cushing's disease.

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