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Forkhead box protein M1 (FOXM1) is often overexpressed in human cancers and strongly associated with therapy resistance and less good patient survival. The chemotherapy options for patients with the most aggressive types of solid cancers remain very limited because of the acquired drug resistance, making the therapy less effective. NPM1 mutation through the inactivation of FOXM1 via FOXM1 relocalization to the cytoplasm confers more favorable treatment outcomes for AML patients, confirming FOXM1 as a crucial target to overcome drug resistance. Pharmacological inhibition of FOXM1 could be a promising approach to sensitize therapy-resistant cancers. Here, we explore a novel FOXM1 inhibitor STL001, a first-generation modification drug of our previously reported FOXM1 inhibitor STL427944. STL001 preserves the mode of action of the STL427944; however, STL001 is up to 50 times more efficient in reducing FOXM1 activity in a variety of solid cancers. The most conventional cancer therapies studied here induce FOXM1 overexpression in solid cancers. The therapy-induced FOXM1 overexpression may explain the failure or reduced efficacy of these drugs in cancer patients. Interestingly, STL001 increased the sensitivity of cancer cells to conventional cancer therapies by suppressing both the high-endogenous and drug-induced FOXM1. Notably, STL001 does not provide further sensitization to FOXM1-KD cancer cells, suggesting that the sensitization effect is conveyed specifically through FOXM1 suppression. RNA-seq and gene set enrichment studies revealed prominent suppression of FOXM1-dependent pathways and gene ontologies. Also, gene regulation by STL001 showed extensive overlap with FOXM1-KD, suggesting a high selectivity of STL001 toward the FOXM1 regulatory network. A completely new activity of FOXM1, mediated through steroid/cholesterol biosynthetic process and protein secretion in cancer cells was also detected. Collectively, STL001 offers intriguing translational opportunities as combination therapies targeting FOXM1 activity in a variety of human cancers driven by FOXM1.
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BACKGROUND: The Fijian 'Bula Smile' is often described as the world's friendliest; however, its description remains anecdotal. OBJECTIVE: This study aimed to describe and compare the dynamics of Fijians' smiles with those of New Zealand Europeans. METHODS: An observational study was conducted on two ethnic groups, Fijians (FJ; N = 23) and New Zealand Europeans (NZ; N = 23), age- and gender-matched. All participants were asked to watch amusing videos, and their reactions were video recorded. The videos were analysed by software to assess the frequency, duration, intensity and genuineness of smiling episodes. Based on the Facial Action Coding System, Action Unit 6 (AU6-cheek raiser), Action Unit 12 (AU12-lip corner puller) and Action Unit 25 (AU25-lips apart) were assessed. Data were analysed by generalised linear models after adjusting for personality traits. RESULTS: Fijians smiled longer than New Zealand Europeans (+19.9%; p = .027). Mean intensity of AU6 (+1.0; 95%CIs = 0.6-1.5; p < .001), AU12 (+0.5; 95%CIs = 0.1-0.9; p = .008) and AU25 (+22.3%; 95%CIs = 7.3%-37.3%; p = .005) were significantly higher in FJ group than the NZ group. CONCLUSION: Smiling features of Fijians and New Zealanders showed objective differences, the most distinctive being a higher activation of the Duchenne's marker (AU6) in the Fijian group, which is regarded as a sign of smile genuineness.
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Sonrisa , Población Blanca , Humanos , Sonrisa/fisiología , Femenino , Masculino , Nueva Zelanda , Adulto , Grabación en Video , Adulto Joven , Pueblo Europeo , Pueblos Isleños del PacíficoRESUMEN
INTRODUCTION: This study aimed to evaluate and compare the performance of 2 artificial intelligence (AI) models, Chat Generative Pretrained Transformer-3.5 (ChatGPT-3.5; OpenAI, San Francisco, Calif) and Google Bidirectional Encoder Representations from Transformers (Google Bard; Bard Experiment, Google, Mountain View, Calif), in terms of response accuracy, completeness, generation time, and response length when answering general orthodontic questions. METHODS: A team of orthodontic specialists developed a set of 100 questions in 10 orthodontic domains. One author submitted the questions to both ChatGPT and Google Bard. The AI-generated responses from both models were randomly assigned into 2 forms and sent to 5 blinded and independent assessors. The quality of AI-generated responses was evaluated using a newly developed tool for accuracy of information and completeness. In addition, response generation time and length were recorded. RESULTS: The accuracy and completeness of responses were high in both AI models. The median accuracy score was 9 (interquartile range [IQR]: 8-9) for ChatGPT and 8 (IQR: 8-9) for Google Bard (Median difference: 1; P <0.001). The median completeness score was similar in both models, with 8 (IQR: 8-9) for ChatGPT and 8 (IQR: 7-9) for Google Bard. The odds of accuracy and completeness were higher by 31% and 23% in ChatGPT than in Google Bard. Google Bard's response generation time was significantly shorter than that of ChatGPT by 10.4 second/question. However, both models were similar in terms of response length generation. CONCLUSIONS: Both ChatGPT and Google Bard generated responses were rated with a high level of accuracy and completeness to the posed general orthodontic questions. However, acquiring answers was generally faster using the Google Bard model.
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Inteligencia Artificial , Ortodoncia , HumanosRESUMEN
Activating estrogen receptor alpha (ER; also known as ESR1) mutations are present in primary endometrial and metastatic breast cancers, promoting estrogen-independent activation of the receptor. Functional characterizations in breast cancer have established unique molecular and phenotypic consequences of the receptor, yet the impact of ER mutations in endometrial cancer has not been fully explored. In this study, we used CRISPR-Cas9 to model the clinically prevalent ER-Y537S mutation and compared results with ER-D538G to discover allele-specific differences between ER mutations in endometrial cancer. We found that constitutive activity of mutant ER resulted in changes in the expression of thousands of genes, stemming from combined alterations to ER binding and chromatin accessibility. The unique gene expression programs resulted in ER-mutant cells developing increased cancer-associated phenotypes, including migration, invasion, anchorage-independent growth, and growth in vivo. To uncover potential treatment strategies, we identified ER-associated proteins via Rapid Immunoprecipitation and Mass Spectrometry of Endogenous Proteins and interrogated two candidates, CDK9 and NCOA3. Inhibition of these regulatory proteins resulted in decreased growth and migration, representing potential novel treatment strategies for ER-mutant endometrial cancer. IMPLICATIONS: This study provides insight into mutant ER activity in endometrial cancer and identifies potential therapies for women with ER-mutant endometrial cancer.
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Neoplasias de la Mama , Neoplasias Endometriales , Femenino , Humanos , Alelos , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Neoplasias de la Mama/patología , Mutación , Neoplasias Endometriales/genética , FenotipoRESUMEN
BACKGROUND: Recent advances in orthodontics offer appealing tools to monitor compliance and designate protocols to enhance it. OBJECTIVE: This systematic review of systematic reviews (SRs) aimed to assess the effectiveness of digitized communication methods and sensor-based devices that track compliance in orthodontic patients. SEARCH METHODS: Five electronic databases (PubMed, Web of Science, MEDLINE, PsycINFO, and EMBASE) were searched from database inception up to 4 December 2022. SELECTION CRITERIA: SRs using digitized systems and sensor-based technologies to monitor and/or improve compliance with orthodontic treatment or during an active retention phase were included. DATA COLLECTION AND ANALYSIS: Study selection, data extraction, and risk of bias assessment using the AMSTAR 2 tool were performed independently by two review authors. A qualitative synthesis of outcomes from moderate- and high-quality SRs was provided, and evidence was graded in accordance with a scale of statements. RESULTS: A total of 846 unique citations were retrieved. After study selection, 18 SRs met the inclusion criteria, and 9 moderate- and high-quality reviews were further integrated into the qualitative synthesis. Digitized communication methods were found to be effective in improving compliance with oral hygiene practices and adherence to orthodontic appointments. Monitoring removable appliance wear with microsensors revealed sub-optimal levels of compliance with wear instructions of intra-oral and extra-oral appliances. One review discussed the informational value of social media platforms and their importance in guiding the decision-making process to seek orthodontic treatment and compliance-related experiences. LIMITATIONS: The variability in the quality of included SRs and the limited number of primary studies on certain outcomes present as limitations within this overview. CONCLUSIONS: The integration of tele-orthodontics and sensor-based technologies to improve and monitor compliance within orthodontic practices is promising. There is sufficient evidence that establishing communication channels with orthodontic patients through reminders and audiovisual systems positively impact their oral hygiene practices throughout orthodontic treatment. However, understanding the informational value of social media as communication channels between clinicians and their patients, and their overall effect on modulating compliance is still insufficient. REGISTRATION: CRD42022331346.
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Ortodoncia , Humanos , Citas y Horarios , Comunicación , Cooperación del Paciente , Revisiones Sistemáticas como AsuntoRESUMEN
Active audiovisual representation of instructions ensures vibrant knowledge acquisition and improves acquaintance needed for self-care with retainer wear. The aim of this trial is to assess the impact of audiovisual instructions with additional weekly electronic reminder messages on improving adherence to instructed wear time of Hawley retainer, periodontal outcomes, and participants' experiences. Fifty-two participants (mean age 26.1 y) planned for removable retention, were randomly assigned to two parallel groups to receive either (1) audiovisual instructions with an additional weekly reminder, or (2) verbal instructions alone. Each participant received a Hawley retainer equipped with a TheraMon microsensor and was instructed to wear it for 22 h daily. Participants were monitored for adherence to the wear time after 3 (T1) and 6 months (T2), and had their periodontal health and experiences assessed at T2. Overall, the mean objectively measured daily wear time at T1 was 14.9 (± 4.9 h), and 14.3 (± 5.4 h) at T2. After 3 months, no significant differences were found between the groups (p = 0.065), however, a significant difference favoring better compliance with wear instructions was observed in the audiovisual group after 6 months (p = 0.033). A non-significant difference was observed between both groups regarding the gingival (p = 0.165) and plaque index scores (p = 0.173). Participants' experiences were similar in both groups, except for satisfaction with the way of delivering instructions, being favorably reported in the audiovisual group. Audiovisual instructions with weekly reminders seem to have a significant effect on patient compliance in the longer term.Trial registration: TCTR20230220002.
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Diseño de Aparato Ortodóncico , Retenedores Ortodóncicos , Humanos , Adulto , Cooperación del Paciente , ElectrónicaRESUMEN
BACKGROUND: Acute gastroenteritis (AGE) can cause acute kidney injury (AKI) via hypoperfusion mechanisms. Early detection of AKI caused by AGE can significantly decrease mortality rates. In Saudi Arabia, studies investigating the association between AGE and AKI are limited; thus, we aimed to fill this knowledge gap. OBJECTIVES: Analyze all cases of AGE reported in tertiary-care hospitals to assess the prevalence of AKI among AGE patients. DESIGN: Retrospective cohort SETTINGS: Single tertiary-care center PATIENTS AND METHODS: The study included patients treated for AGE between October 2017 and October 2022. Stool culture was used to diagnose AGE. Inclusion criteria were infective diarrhea and/ or vomiting, and availability of data (demographics, comorbidities, malignancies, length of hospital stay, vital signs at the time of diagnosis, dehydration, causative agents of diarrhea, hemodialysis status, and laboratory data. MAIN OUTCOME MEASURES: Prevalence of AKI among AGE patients and factors associated with development of AKI. SAMPLE SIZE: 300 patients diagnosed with AGE. RESULTS: Of the 300 patients with AGE, 41 (13.6%) had AKI, those older than 60 years were more likely to develop AKI. The most frequent cause of AGE was Salmonella spp. (n=163, 53.3%), whereas AKI was most common in Clostridium difficile AGE patients (n=21, 51.2%). Furthermore, the most common comorbidity in the present study was malignancy, especially leukemia and lymphoma the risk of AKI was independently associated with mild dehydration, higher serum urea concentrations and low GFR values. CONCLUSIONS: Patients hospitalized for diarrheal disease are at an increased risk of developing AKI due to dehydration and comorbid conditions. It is crucial to keep kidney function in mind for AGE patients as this is associated with a high mortality rate and poor prognosis. LIMITATIONS: The main limitation of this study was its retrospective design. Another limitation is that it is limited to a single center. CONFLICTS OF INTEREST: None.
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Lesión Renal Aguda , Gastroenteritis , Humanos , Adulto , Estudios Retrospectivos , Centros de Atención Terciaria , Deshidratación/complicaciones , Deshidratación/epidemiología , Gastroenteritis/complicaciones , Gastroenteritis/epidemiología , Diarrea/epidemiología , Diarrea/etiología , Lesión Renal Aguda/epidemiología , Lesión Renal Aguda/etiología , Lesión Renal Aguda/diagnóstico , Factores de Riesgo , Mortalidad HospitalariaRESUMEN
INTRODUCTION: This observational study investigated the relationship between malocclusion and smiling. METHODS: Adolescents and young adults (n = 72; aged 16-25 years) were identified according to their Dental Aesthetic Index (DAI) and allocated to 3 groups: (1) malocclusion group (n = 24; DAI ≥31), (2) retention group (n = 24; pretreatment DAI ≥31) with a prior malocclusion that had been corrected by orthodontic treatment, (3) control group with no-to-minor malocclusion (n = 24; DAI ≤25). Participants were requested to watch an amusing video. Based on the Facial Action Coding System, automated pattern recognition was used to detect smile episodes and assess their frequency, duration, genuineness, intensity, and extent of tooth show. Demographics, Big Five personality dimensions, and self-perceived smile esthetics-related quality of life were collected from all participants via questionnaires. Data were analyzed by mixed-model analysis and adjusted for possible confounders. RESULTS: Patients from the malocclusion and retention groups smiled significantly less than participants from the control group, with the duration of smiles and smiling time being around half those of control subjects. Smile genuineness, smile intensity, and teeth shown did not differ across groups. Personality traits did not differ significantly among the 3 groups, whereas the malocclusion group scored around 30% less for dental self-confidence than the other 2 groups. CONCLUSIONS: Patients with severe malocclusion tend to smile less, but the features of their smiles are similar to those without malocclusion. A lower propensity to smile in patients with a corrected malocclusion may persist after orthodontic treatment.
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Maloclusión , Sonrisa , Adolescente , Adulto Joven , Humanos , Calidad de Vida , Estética Dental , Maloclusión/terapia , AutoimagenRESUMEN
Overexpression of the HER2 protein in breast cancer patients is a predictor of poor prognosis and resistance to therapies. We used an inducible breast cancer transformation system that allows investigation of early molecular changes. HER2 overexpression to similar levels as those observed in a subtype of HER2-positive breast cancer patients induced transformation of MCF10A cells and resulted in gross morphological changes, increased anchorage-independent growth of cells, and altered the transcriptional programme of genes associated with oncogenic transformation. Global phosphoproteomic analysis during HER2 induction predominantly detected an increase in protein phosphorylation. Intriguingly, this correlated with chromatin opening, as measured by ATAC-seq on acini isolated from 3D cell culture. HER2 overexpression resulted in opening of many distal regulatory regions and promoted reprogramming-associated heterogeneity. We found that a subset of cells acquired a dedifferentiated breast stem-like phenotype, making them likely candidates for malignant transformation. Our data show that this population of cells, which counterintuitively enriches for relatively low HER2 protein abundance and increased chromatin accessibility, possesses transformational drive, resulting in increased anchorage-independent growth in vitro compared to cells not displaying a stem-like phenotype.
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Cromatina , Receptor ErbB-2 , Humanos , Receptor ErbB-2/genética , Proliferación Celular , Transformación Celular Neoplásica/genética , Epitelio/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. However, the role of ASXL1 in myeloid lineage maturation is incompletely described. To define the role of ASXL1 in myelopoiesis, we employed single cell RNA sequencing and a murine model of hematopoietic-specific Asxl1 deletion. In granulocyte progenitors, Asxl1 deletion leads to hyperactivation of MYC and a quantitative decrease in neutrophil production. This loss of granulocyte production was not accompanied by significant changes in the landscape of covalent histone modifications. However, Asxl1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription. These results suggest that ASXL1 inhibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator in myeloid development.
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Síndromes Mielodisplásicos , ARN Polimerasa II , Proteínas Represoras , Animales , Humanos , Ratones , Células Precursoras de Granulocitos/patología , Mutación , Síndromes Mielodisplásicos/genética , Proteínas Represoras/genética , ARN Polimerasa II/genética , Factores de Transcripción/genéticaRESUMEN
OBJECTIVE: This randomized controlled trial (RCT) aims to investigate the short-term effects of chlorhexidine mouthwash (MW) on gingival health surrounding orthodontic miniscrew implants (OMIs) and their overall survivability. MATERIALS AND METHODS: Thirty-two participants (mean age, 22.8 years) undergoing fixed orthodontic appliance treatment after maxillary premolar extraction were randomly allocated in a parallel fashion to either receive (1) MW with an active component of chlorhexidine or (2) a placebo. Each participant received two maxillary buccal OMIs for anchorage reinforcement purposes. Participants were assessed for their gingival oral health status around all inserted OMIs and had their OMI survivability recorded at three time points; T1 = 1 month, T2 = 3 months, and T3 = 6 months after OMI placement. A Kaplan-Meier plot was used to estimate the survival function of OMIs. RESULTS: All randomized participants completed the follow-up period. In terms of gingival oral health, there were no statistically significant differences at any time point between the chlorhexidine MW group and the placebo-controlled group (P > .05). One OMI was lost in the chlorhexidine MW group and another two OMIs in the control group. There was no significant difference between both groups in terms of survivability (P = .585). CONCLUSION: The use of chlorhexidine MW does not seem to have a significant clinical impact on gingival health around OMIs or their survivability in this pilot study.
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Clorhexidina , Antisépticos Bucales , Humanos , Adulto Joven , Adulto , Clorhexidina/uso terapéutico , Antisépticos Bucales/uso terapéutico , Aparatos Ortodóncicos Fijos , Índice de Placa Dental , Índice PeriodontalRESUMEN
Background Interoception refers to the cognitive process of perceiving internal bodily states. This encompasses various physiological indicators, including heart rate fluctuations, stomach distention, internal temperature, hydration levels, sensory input from free nerve terminals in the fascia and muscles, as well as hormonal, stretch, and pain receptors. This study aimed to examine the interoceptive awareness among the general public in Saudi Arabia. Methods A cross-sectional online survey was undertaken in Saudi Arabia to investigate the level of interoceptive awareness within the overall population of the country in October 2023. This research used a previously developed questionnaire named the Multidimensional Assessment of Interoceptive Awareness, version 2 (MAIA-2). In a binary logistic regression analysis, the mean interoceptive awareness score of the participants was utilized as the dummy variable to determine the variables that influence interoceptive awareness. Results A total of 814 participants were involved in this study. Overall, the study participants demonstrated a marginal level of interoceptive awareness with a mean score of 94.3 (standard deviation (SD): 29.3) out of 185 (representing 51.0% of the maximum attainable score). The mean interoceptive score was not consistent across different subscales and ranged between 37.7% and 63.3%. The highest mean interoceptive score was observed for the Trusting subscale (9.5 (SD: 4.5) out of 15) (representing 63.3% of the maximum attainable score for this subscale). The lowest mean interoceptive score was observed for the Not-Distracting subscale (11.3 (SD: 6.9) out of 30) (representing 37.7% of the maximum attainable score for this subscale). Binary logistic regression analysis did not identify any statistically significant difference in the likelihood of having a higher level of interoceptive awareness among the participants based on their demographic characteristics (p>0.05). Conclusion The participants in our research demonstrated a modest degree of interoceptive awareness. The study's results suggest that the participants demonstrated a heightened inclination towards internal experiences rather than being attentive to their bodily sensations. Further investigation is required to examine interoceptive awareness across various cohorts.
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Breast cancers are known to be driven by the transcription factor estrogen receptor and its ligand estrogen. While the receptor's cis-binding elements are known to vary between tumors, heterogeneity of hormone signaling at a single-cell level is unknown. In this study, we systematically tracked estrogen response across time at a single-cell level in multiple cell line and organoid models. To accurately model these changes, we developed a computational tool (TITAN) that quantifies signaling gradients in single-cell datasets. Using this approach, we found that gene expression response to estrogen is non-uniform, with distinct cell groups expressing divergent transcriptional networks. Pathway analysis suggested the two most distinct signatures are driven separately by ER and FOXM1. We observed that FOXM1 was indeed activated by phosphorylation upon estrogen stimulation and silencing of FOXM1 attenuated the relevant gene signature. Analysis of scRNA-seq data from patient samples confirmed the existence of these divergent cell groups, with the FOXM1 signature predominantly found in ER negative cells. Further, multi-omic single-cell experiments indicated that the different cell groups have distinct chromatin accessibility states. Our results provide a comprehensive insight into ER biology at the single-cell level and potential therapeutic strategies to mitigate resistance to therapy.
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Neoplasias de la Mama , Epigénesis Genética , Estrógenos , Femenino , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Estrógenos/farmacología , Regulación Neoplásica de la Expresión Génica , Receptores de Estrógenos/metabolismo , Análisis de la Célula Individual , RNA-SeqRESUMEN
BACKGROUND: Patients seeking restorative and orthodontic treatment expect an improvement in their smiles and oral health-related quality of life. Nonetheless, the qualitative and quantitative characteristics of dynamic smiles are yet to be understood. OBJECTIVE: To develop, validate, and introduce open-access software for automated analysis of smiles in terms of their frequency, genuineness, duration, and intensity. MATERIALS AND METHODS: A software script was developed using the Facial Action Coding System (FACS) and artificial intelligence to assess activations of (1) cheek raiser, a marker of smile genuineness; (2) lip corner puller, a marker of smile intensity; and (3) perioral lip muscles, a marker of lips apart. Thirty study participants were asked to view a series of amusing videos. A full-face video was recorded using a webcam. The onset and cessation of smile episodes were identified by two examiners trained with FACS coding. A Receiver Operating Characteristic (ROC) curve was then used to assess detection accuracy and optimise thresholding. The videos of participants were then analysed off-line to automatedly assess the features of smiles. RESULTS: The area under the ROC curve for smile detection was 0.94, with a sensitivity of 82.9% and a specificity of 89.7%. The software correctly identified 90.0% of smile episodes. While watching the amusing videos, study participants smiled 1.6 (±0.8) times per minute. CONCLUSIONS: Features of smiles such as frequency, duration, genuineness, and intensity can be automatedly assessed with an acceptable level of accuracy. The software can be used to investigate the impact of oral conditions and their rehabilitation on smiles.
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Inteligencia Artificial , Calidad de Vida , Humanos , Expresión Facial , Sonrisa/fisiología , LabioRESUMEN
This study aimed to investigate the antidepressant property of crocin (Crocetin digentiobiose ester) using a chronic mild stress (CMS)-induced depression model in experimental mice. The tail suspension test (TST) and the sucrose preference test were used to evaluate the antidepressant effect on albino mice of either sex after three weeks of CMS. The period of immobility in the TST and percentage preference for sucrose solution were recorded. By monitoring brain malondialdehyde (MDA) level, catalase (CAT) activity, and reduced glutathione (GSH) level, the antioxidant potential was assessed. Three dosages of crocin (4.84, 9.69, and 19.38 mg/kg) were evaluated. When compared to controls, animals that received crocin administration during three periods of CMS had considerably shorter immobility times during the TST. Crocin treatment also raised the percentage preference for sucrose solution in a dose-dependent manner, bringing it to parity with the conventional antidepressant, imipramine. Animals that received a high dose of crocin had a much greater spontaneous locomotor activity. Furthermore, a high dose of crocin remarkably lowered plasma corticosterone and nitrite levels brought on by CMS. Additionally, high doses of crocin given during CMS greatly enhanced reduced glutathione levels while considerably reducing the brain's MDA and catalase activities. In conclusion, high doses of crocin may have an antidepressant effect in an animal model through several mechanisms. However, further studies should be carried out to explore the role of neurotransmitters for their antidepressant property.
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Antidepresivos , Depresión , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Antioxidantes/farmacología , Conducta Animal , Carotenoides , Catalasa/farmacología , Depresión/tratamiento farmacológico , Depresión/etiología , Modelos Animales de Enfermedad , Glutatión/farmacología , Ratones , Estrés Psicológico/tratamiento farmacológico , Sacarosa/farmacologíaRESUMEN
BACKGROUND: Patients who undergo living donor liver transplantation (LDLT) may suffer complications that require intensive care unit (ICU) readmission. AIM: To identify the incidence, causes, and outcomes of ICU readmission after LDLT. METHODS: A retrospective cohort study was conducted on patients who underwent LDLT. The collected data included patient demographics, preoperative characteristics, intraoperative details; postoperative stay, complications, causes of ICU readmission, and outcomes. Patients were divided into two groups according to ICU readmission after hospital discharge. Risk factors for ICU readmission were identified in univariate and multivariate analyses. RESULTS: The present study included 299 patients. Thirty-one (10.4%) patients were readmitted to the ICU after discharge. Patients who were readmitted to the ICU were older in age (53.0 ± 5.1 vs 49.4 ± 8.8, P = 0.001) and had a significantly higher percentage of women (29% vs 13.4%, P = 0.032), diabetics (41.9% vs 24.6%, P = 0.039), hypertensives (22.6% vs 6.3%, P = 0.006), and renal (6.5% vs 0%, P = 0.010) patients as well as a significantly longer initial ICU stay (6 vs 4 d, respectively, P < 0.001). Logistic regression analysis revealed that significant independent risk factors for ICU readmission included recipient age (OR = 1.048, 95%CI = 1.005-1.094, P = 0.030) and length of initial hospital stay (OR = 0.836, 95%CI = 0.789-0.885, P < 0.001). CONCLUSION: The identification of high-risk patients (older age and shorter initial hospital stay) before ICU discharge may help provide optimal care and tailor follow-up to reduce the rate of ICU readmission.
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Most invasive lobular breast cancers (ILC) are of the luminal A subtype and are strongly hormone receptor-positive. Yet, ILC is relatively resistant to tamoxifen and associated with inferior long-term outcomes compared with invasive ductal cancers (IDC). In this study, we sought to gain mechanistic insights into these clinical findings that are not explained by the genetic landscape of ILC and to identify strategies to improve patient outcomes. A comprehensive analysis of the epigenome of ILC in preclinical models and clinical samples showed that, compared with IDC, ILC harbored a distinct chromatin state linked to gained recruitment of FOXA1, a lineage-defining pioneer transcription factor. This resulted in an ILC-unique FOXA1-estrogen receptor (ER) axis that promoted the transcription of genes associated with tumor progression and poor outcomes. The ILC-unique FOXA1-ER axis led to retained ER chromatin binding after tamoxifen treatment, which facilitated tamoxifen resistance while remaining strongly dependent on ER signaling. Mechanistically, gained FOXA1 binding was associated with the autoinduction of FOXA1 in ILC through an ILC-unique FOXA1 binding site. Targeted silencing of this regulatory site resulted in the disruption of the feed-forward loop and growth inhibition in ILC. In summary, ILC is characterized by a unique chromatin state and FOXA1-ER axis that is associated with tumor progression, offering a novel mechanism of tamoxifen resistance. These results underscore the importance of conducting clinical trials dedicated to patients with ILC in order to optimize treatments in this breast cancer subtype. SIGNIFICANCE: A unique FOXA1-ER axis in invasive lobular breast cancer promotes disease progression and tamoxifen resistance, highlighting a potential therapeutic avenue for clinical investigations dedicated to this disease. See related commentary by Blawski and Toska, p. 3668.
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Neoplasias de la Mama , Carcinoma Ductal de Mama , Carcinoma Lobular , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Cromatina/genética , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Pronóstico , Receptores de Estrógenos/metabolismo , Tamoxifeno/farmacología , Tamoxifeno/uso terapéuticoRESUMEN
INTRODUCTION: Coronavirus disease 2019 (COVID-19) is one of the most formidable challenges that influenced all domains of health care delivery. This research explored the experiences and challenges orthodontic patients faced in quarantine during the COVID-19 outbreak. The goal was to learn from patients about their oral health and general practices during this time to provide optimal delivery of orthodontic treatment care. METHODS: A phenomenographic qualitative design involving semistructured face-to-face interviews. A purposive sampling strategy was deployed to collect qualitative data from 24 orthodontic patients who quarantined during the COVID-19 pandemic. All interviews were digitally recorded, and afterwards, they were transcribed verbatim. RESULTS: Four main themes and associated subthemes were identified. The themes were (1) oral-health-related behavioral changes, (2) impact on treatment progression, (3) psychosocial impact and attitude changes, and (4) areas for future enhancements in health care delivery. Overall findings revealed both positive and negative behavioral changes in orthodontic patients regarding their adjustment during the quarantine and its implications to general health and well-being. CONCLUSIONS: Findings from this study suggest that COVID-19 impacted dental health care delivery to orthodontic patients during the quarantine. Patients reported psychosocial and behavioral changes as a consequence of treatment disruption and pandemic lockdown. The implications of these findings to the clinical dental environment and patient education are pivotal to further target areas in dental health care delivery that require strengthening. As such, clinicians could expect behavioral changes from orthodontic patients and identify better strategies to mitigate clinical challenges resulting from such changes.
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COVID-19 , Cuarentena , Control de Enfermedades Transmisibles/métodos , Humanos , Pandemias/prevención & control , Investigación Cualitativa , Cuarentena/psicología , SARS-CoV-2RESUMEN
The evolution of opposable thumb has enabled fine grasping ability and precision grip, therefore the ability to finely manipulate the objects and refined tool use. Since tactile inputs to an opposable thumb are often spatially and temporally out of sync with inputs from the fingers, we hypothesized that inputs from the opposable thumb would be processed in an independent module in the primary somatosensory cortex (area 3b). Here we show that in area 3b of macaque monkeys, most neurons in the thumb representation do not respond to tactile stimulation of other digits and receive few intrinsic cortical inputs from other digits. However, neurons in the representations of other 4 digits respond to touch on any of the 4 digits and interconnect significantly more. The thumb inputs are thus processed in an independent module, whereas there is a significantly more interdigital information exchange between the other digits. This cortical organization reflects behavioral use of a hand with an opposable thumb.