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Telomeres are nucleoprotein structures at the end of chromosomes that maintain their integrity. Mutations in genes coding for proteins involved in telomere protection and elongation produce diseases such as dyskeratosis congenita or idiopathic pulmonary fibrosis known as telomeropathies. These diseases are characterized by premature telomere shortening, increased DNA damage and oxidative stress. Genetic diagnosis of telomeropathy patients has identified mutations in the genes TERT and TERC coding for telomerase components but the functional consequences of many of these mutations still have to be experimentally demonstrated. The activity of twelve TERT and five TERC mutants, five of them identified in Spanish patients, has been analyzed. TERT and TERC mutants were expressed in VA-13 human cells that express low telomerase levels and the activity induced was analyzed. The production of reactive oxygen species, DNA oxidation and TRF2 association at telomeres, DNA damage response and cell apoptosis were determined. Most mutations presented decreased telomerase activity, as compared to wild-type TERT and TERC. In addition, the expression of several TERT and TERC mutants induced oxidative stress, DNA oxidation, DNA damage, decreased recruitment of the shelterin component TRF2 to telomeres and increased apoptosis. These observations might indicate that the increase in DNA damage and oxidative stress observed in cells from telomeropathy patients is dependent on their TERT or TERC mutations. Therefore, analysis of the effect of TERT and TERC mutations of unknown function on DNA damage and oxidative stress could be of great utility to determine the possible pathogenicity of these variants.
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Disqueratosis Congénita , Telomerasa , Humanos , Apoptosis/genética , ADN/metabolismo , Daño del ADN/genética , Disqueratosis Congénita/genética , Disqueratosis Congénita/metabolismo , Disqueratosis Congénita/patología , Mutación , Estrés Oxidativo/genética , ARN/genética , Telomerasa/genética , Telomerasa/metabolismo , Telómero/genética , Telómero/metabolismoRESUMEN
Both the spindle microtubule-organizing centers and the nuclear pore complexes (NPCs) are convoluted structures where many signaling pathways converge to coordinate key events during cell division. Interestingly, despite their distinct molecular conformation and overall functions, these structures share common components and collaborate in the regulation of essential processes. We have established a new link between microtubule-organizing centers and nuclear pores in budding yeast by unveiling an interaction between the Bfa1/Bub2 complex, a mitotic exit inhibitor that localizes on the spindle pole bodies, and the Nup159 nucleoporin. Bfa1/Bub2 association with Nup159 is reduced in metaphase to not interfere with proper spindle positioning. However, their interaction is stimulated in anaphase and assists the Nup159-dependent autophagy pathway. The asymmetric localization of Bfa1/Bub2 during mitosis raises the possibility that its interaction with Nup159 could differentially promote Nup159-mediated autophagic processes, which might be relevant for the maintenance of the replicative lifespan.
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Proteínas de Ciclo Celular , Proteínas de Saccharomyces cerevisiae , Proteínas de Ciclo Celular/metabolismo , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Complejo Poro Nuclear/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Cuerpos Polares del Huso/metabolismo , Proteínas del Citoesqueleto/metabolismo , Huso Acromático/genética , Huso Acromático/metabolismo , Mitosis/genéticaRESUMEN
Chromosomal fusions represent one of the most common types of chromosomal rearrangements found in nature. Yet, their role in shaping the genomic landscape of recombination and hence genome evolution remains largely unexplored. Here, we take advantage of wild mice populations with chromosomal fusions to evaluate the effect of this type of structural variant on genomic landscapes of recombination and divergence. To this aim, we combined cytological analysis of meiotic crossovers in primary spermatocytes with inferred analysis of recombination rates based on linkage disequilibrium using single nucleotide polymorphisms. Our results suggest the presence of a combined effect of Robertsonian fusions and Prdm9 allelic background, a gene involved in the formation of meiotic double strand breaks and postzygotic reproductive isolation, in reshaping genomic landscapes of recombination. We detected a chromosomal redistribution of meiotic recombination toward telomeric regions in metacentric chromosomes in mice with Robertsonian fusions when compared to nonfused mice. This repatterning was accompanied by increased levels of crossover interference and reduced levels of estimated recombination rates between populations, together with high levels of genomic divergence. Interestingly, we detected that Prdm9 allelic background was a major determinant of recombination rates at the population level, whereas Robertsonian fusions showed limited effects, restricted to centromeric regions of fused chromosomes. Altogether, our results provide new insights into the effect of Robertsonian fusions and Prdm9 background on meiotic recombination.
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Cromosomas , Genómica , Masculino , Animales , Ratones , AlelosRESUMEN
Glycosylation is recognized as a key process for proper megakaryopoiesis and platelet formation. The enzyme uridine diphosphate (UDP)-galactose-4-epimerase, encoded by GALE, is involved in galactose metabolism and protein glycosylation. Here, we studied 3 patients from 2 unrelated families who showed lifelong severe thrombocytopenia, bleeding diathesis, mental retardation, mitral valve prolapse, and jaundice. Whole-exome sequencing revealed 4 variants that affect GALE, 3 of those previously unreported (Pedigree A, p.Lys78ValfsX32 and p.Thr150Met; Pedigree B, p.Val128Met; and p.Leu223Pro). Platelet phenotype analysis showed giant and/or grey platelets, impaired platelet aggregation, and severely reduced alpha and dense granule secretion. Enzymatic activity of the UDP-galactose-4-epimerase enzyme was severely decreased in all patients. Immunoblotting of platelet lysates revealed reduced GALE protein levels, a significant decrease in N-acetyl-lactosamine (LacNAc), showing a hypoglycosylation pattern, reduced surface expression of gylcoprotein Ibα-IX-V (GPIbα-IX-V) complex and mature ß1 integrin, and increased apoptosis. In vitro studies performed with patients-derived megakaryocytes showed normal ploidy and maturation but decreased proplatelet formation because of the impaired glycosylation of the GPIbα and ß1 integrin, and reduced externalization to megakaryocyte and platelet membranes. Altered distribution of filamin A and actin and delocalization of the von Willebrand factor were also shown. Overall, this study expands our knowledge of GALE-related thrombocytopenia and emphasizes the critical role of GALE in the physiological glycosylation of key proteins involved in platelet production and function.
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Trombocitopenia , UDPglucosa 4-Epimerasa , Humanos , Plaquetas/metabolismo , Galactosa/metabolismo , Glicosilación , Integrina beta1/metabolismo , Megacariocitos/metabolismo , Trombocitopenia/genética , Trombocitopenia/metabolismo , Trombopoyesis/genética , UDPglucosa 4-Epimerasa/genética , UDPglucosa 4-Epimerasa/metabolismo , Uridina Difosfato/metabolismoRESUMEN
BACKGROUND: The first approvals of novel systemic therapies within recent years for metastatic hormone-sensitive (mHSPC) were mainly based on improved overall survival (OS) and time to castration resistance (ttCRPC) in mHSPC patients stratified according to CHAARTED low (LV) versus high volume (HV) and LATITUDE low (LR) versus high-risk (HR) disease. METHODS: Relying on our institutional tertiary-care database we identified all mHSPC stratified according to CHAARTED LV versus HV, LATITUDE LR versus HR and the location of the metastatic spread (lymph nodes (M1a) versus bone (M1b) versus visceral/others (M1c) metastases. OS and ttCRPC analyses, as well as Cox regression models were performed according to different metastatic categories. RESULTS: Of 451 mHSPC, 14% versus 27% versus 48% versus 12% were classified as M1a LV versus M1b LV versus M1b HV versus M1c HV with significant differences in median OS: 95 versus 64 versus 50 versus 46 months (p < 0.001). In multivariable Cox regression models HV M1b (Hazard Ratio: 2.4, p = 0.03) and HV M1c (Hazard Ratio: 3.3, p < 0.01) harbored significant worse than M1a LV mHSPC. After stratification according to LATITUDE criteria, also significant differences between M1a LR versus M1b LR versus M1b HR versus M1c HR mHSPC patients were observed (p < 0.01) with M1b HR (Hazard Ratio: 2.7, p = 0.03) and M1c HR (Hazard Ratio: 3.5, p < 0.01), as predictor for worse OS. In comparison between HV M1b and HV M1c, as well as HR M1b versus HR M1c no differences in ttCRPC or OS were observed. CONCLUSIONS: Significant differences exist between different metastatic patterns of HV and LV and HR and LR criteria. Best prognosis is observed within M1a LV and LR mHSPC patients.
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BACKGROUND: To evaluate the impact of prostate-specific antigen (PSA) nadir, PSA response and time to PSA nadir (TTN) in metastatic hormone-sensitive prostate cancer (mHSPC) patients on overall survival (OS) in the era of combination therapies. METHODS: Different PSA nadir cut-offs (including ultra-low PSA) were tested for OS analyses. Additionally, PSA response ≥99% was evaluated, as well as TTN categorized as <3 versus 3-6 versus 6-12 versus >12 months. Multivariable Cox regression models predicted the value of PSA nadir cut-offs, PSA response and TTN on OS. Sensitivity analyses were performed in de novo and high volume mHSPC patients. RESULTS: Of 238 eligible patients, PSA cut-offs of <0.2 versus 0.2-4.0 versus >4.0 ng/mL differed significantly regarding median OS (96 vs. 56 vs. 44 months, p < 0.01), as well as in subgroup analyses of de novo mHSPC patients and multivariable Cox regression models. A more stringent PSA cut-off of <0.02 versus 0.02-0.2 versus >0.2 ng/mL also yielded significant median OS differences (not reached vs. 96 vs. 50 months, p < 0.01), even after additional multivariable adjustment. A PSA response ≥99% was also significantly associated with better OS than counterparty with <99% response, even after multivariable adjustment (both p < 0.02). When TTN groups were compared, patients with longer TTN harbored more extended OS than those with short TTN (<3 vs. 3-6 vs. 6-12 vs. >12 months: 34 vs. 50 vs. 67 vs. 96 months, p < 0.01). Virtually similar results were observed in sensitivity analyses for high volume mHSPC patients. CONCLUSIONS: In times of combination therapies for mHSPC, a PSA nadir of respectively, <0.2 and <0.02 ng/mL are associated with best OS rates. Moreover, a relative PSA response ≥99% and a longer TTN are clinical important proxies for favorable OS estimates.
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Antígeno Prostático Específico , Neoplasias de la Próstata , Humanos , Masculino , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Anciano , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Retrospectivos , Factores de TiempoRESUMEN
The prevalence of obesity has increased considerably in the last few decades. Pathophysiological changes in obese patients lead to pharmacokinetic (PK) and pharmacodynamic (PD) alterations that can condition the correct exposure to antimicrobials if standard dosages are used. Inadequate dosing in obese patients can lead to toxicity or therapeutic failure. In recent years, additional antimicrobial PK/PD data, extended infusion strategies, and studies in critically ill patients have made it possible to obtain data to provide a better dosage in obese patients. Despite this, it is usually difficult to find information on drug dosing in this population, which is sometimes contradictory. This is a comprehensive review of the dosing of different types of antimicrobials (antibiotics, antifungals, antivirals, and antituberculosis drugs) in obese patients, where the literature on PK and possible dosing strategies in obese adults was critically assessed.
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Antibacterianos , Obesidad , Humanos , Antibacterianos/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Antiinfecciosos/farmacocinética , Antiinfecciosos/administración & dosificación , Antiinfecciosos/uso terapéutico , Antifúngicos/farmacocinética , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Antituberculosos/farmacocinética , Antituberculosos/administración & dosificación , Antituberculosos/uso terapéutico , Antivirales/farmacocinética , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Enfermedad Crítica , Obesidad/tratamiento farmacológicoRESUMEN
Lymphoepithelioma-like urothelial carcinoma of the urinary bladder (LELC-B) is a rare histologic subtype characterized by strong immune cell infiltrates. A better prognosis and favorable response rates to immune-checkpoint inhibitors (ICI) have been described. We aimed to characterize the molecular profiles and immune cell infiltration of LELC-B for a better understanding and its therapeutic implications. We identified eleven muscle-invasive bladder cancer cases with pure and mixed LELC-B. PD-L1 expression and mismatch-repair (MMR) proteins were evaluated using immunohistochemistry. We calculated the tumor-mutational burden (TMB) and characterized mutational profiles using whole exome DNA-sequencing data. Transcriptomic signatures were detected using the NanoString nCounter PanCancer IO360 panel. Multiplex immunofluorescence of tumor microenvironment (PD-L1, PanCK, aSMA, Vimentin, CD45, Ki67) and T-cells (CD4, CD3, PD-1, CD163, CD8, FoxP3) was used to quantify cell populations. All LELC-B cases were highly positive for PD-L1 (median TPS/TC 70%; range 20-100; median CPS 100; range 50-100), MMR-proficient and negative for Epstein-Barr virus infection. Immune cell infiltrates were characterized by high CD8+ T-cell count and high PD-1/PD-L1 expression on immune and tumor cells. LELC-B showed upregulation of signaling pathways involved in immune cell response. Most common mutations were found in chromatin remodeling genes causing epigenetic dysregulation. All LELC-B cases showed high TMB of 39 Mut/Mb (IQR 29-66). In conclusion, LELC-B is a highly immunogenic tumor, showing strong upregulation of PD1/PD-L1 and making ICI a promising treatment option.
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BACKGROUND: In contemporary surgically treated patients with localized high-grade (G3 or G4) clear-cell renal cell carcinoma (ccRCC), it is not known whether presence of sarcomatoid dedifferentiation is an independent predictor and/or an effect modifier, when cancer-specific mortality (CSM) represents an endpoint. METHODS: Within the Surveillance, Epidemiology, and End Results database, all surgically treated localized high-grade ccRCC patients treated between 2010 and 2020 were identified. Univariable and multivariable Cox-regression models were used. RESULTS: In 18,853 surgically treated localized high-grade (G3 or G4) ccRCC patients, 5-year CSM-free survival was 87% (62% vs. 88% with vs. without sarcomatoid dedifferentiation, p < 0.001). Presence of sarcomatoid dedifferentiation was an independent predictor of higher CSM (hazard ratio [HR] 1.8, p < 0.001). In univariable survival analyses predicting CSM, presence versus absence of sarcomatoid dedifferentiation in G3 versus G4 yielded the following hazard ratios: HR 1.0 in absent sarcomatoid dedifferentiation in G3; HR 2.7 (p < 0.001) in absent sarcomatoid dedifferentiation in G4; HR 3.9 (p < 0.001) in present sarcomatoid dedifferentiation in G3; HR 5.1 (p < 0.001) in present sarcomatoid dedifferentiation in G4. Finally, in multivariable Cox-regression analyses, the interaction terms defining present versus absent sarcomatoid dedifferentiation in G3 versus G4 represented independent predictors of higher CSM. CONCLUSIONS: In contemporary surgically treated patients with localized high-grade ccRCC, sarcomatoid dedifferentiation is not only an independent multivariable predictor of higher CSM, but also interacts with tumor grade and results in even better ability to predict CSM.
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Carcinoma de Células Renales , Desdiferenciación Celular , Neoplasias Renales , Humanos , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/mortalidad , Masculino , Femenino , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Tasa de Supervivencia , Anciano , Persona de Mediana Edad , Pronóstico , Estudios de Seguimiento , Programa de VERF , Nefrectomía/mortalidad , Clasificación del TumorRESUMEN
BACKGROUND: A significant proportion of people with clozapine-treated schizophrenia develop 'checking' compulsions, a phenomenon yet to be understood. AIMS: To use habit formation models developed in cognitive neuroscience to investigate the dynamic interplay between psychosis, clozapine dose and obsessive-compulsive symptoms (OCS). METHOD: Using the anonymised electronic records of a cohort of clozapine-treated patients, including longitudinal assessments of OCS and psychosis, we performed longitudinal multi-level mediation and multi-level moderation analyses to explore associations of psychosis with obsessiveness and excessive checking. Classic bivariate correlation tests were used to assess clozapine load and checking compulsions. The influence of specific genetic variants was tested in a subsample. RESULTS: A total of 196 clozapine-treated individuals and 459 face-to-face assessments were included. We found significant OCS to be common (37.9%), with checking being the most prevalent symptom. In mediation models, psychosis severity mediated checking behaviour indirectly by inducing obsessions (r = 0.07, 95% CI 0.04-0.09; P < 0.001). No direct effect of psychosis on checking was identified (r = -0.28, 95% CI -0.09 to 0.03; P = 0.340). After psychosis remission (n = 65), checking compulsions correlated with both clozapine plasma levels (r = 0.35; P = 0.004) and dose (r = 0.38; P = 0.002). None of the glutamatergic and serotonergic genetic variants were found to moderate the effect of psychosis on obsession and compulsion (SLC6A4, SLC1A1 and HTR2C) survived the multiple comparisons correction. CONCLUSIONS: We elucidated different phases of the complex interplay of psychosis and compulsions, which may inform clinicians' therapeutic decisions.
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Antipsicóticos , Clozapina , Trastornos Psicóticos , Esquizofrenia Resistente al Tratamiento , Humanos , Clozapina/efectos adversos , Clozapina/uso terapéutico , Masculino , Femenino , Adulto , Antipsicóticos/efectos adversos , Estudios Longitudinales , Trastornos Psicóticos/tratamiento farmacológico , Esquizofrenia Resistente al Tratamiento/tratamiento farmacológico , Esquizofrenia Resistente al Tratamiento/genética , Persona de Mediana Edad , Conducta Compulsiva/inducido químicamente , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Trastorno Obsesivo Compulsivo/inducido químicamente , Esquizofrenia/tratamiento farmacológicoRESUMEN
RESEARCH QUESTION: Does rescue in-vitro maturation (IVM) in the presence or absence of cumulus cells, affect the progress of meiosis I, compared with oocytes that mature in vivo? DESIGN: This prospective study was conducted in a university-affiliated fertility centre. Ninety-five young oocyte donors (mean age 25.57 ± 4.47) with a normal karyotype and no known fertility problems were included. A total of 390 oocytes (116 mature metaphase II [MII] and 274 immature oocytes) were analysed. The immature oocytes underwent rescue IVM in the presence of cumulus cells (CC; IVM+CC; nâ¯=â¯137) or without them (IVM-CC; nâ¯=â¯137), and IVM rate was calculated. Chromosome copy number analysis using next-generation sequencing (NGS) was performed on all rescue IVM oocytes reaching MII as well as those that were mature at the time of initial denudation (in-vivo-matured oocytes [IVO]). RESULTS: Maturation rates were similar in IVM+CC and IVM-CC oocytes (62.8 versus 71.5%, Pâ¯=â¯0.16). Conclusive cytogenetic results were obtained from 65 MII oocytes from the IVM+CC group, 87 from the IVM-CC group, and 99 from the IVO group. Oocyte euploidy rates for the three groups were similar, at 75.4%, 83.9% and 80.8%, respectively (Pâ¯=â¯0.42). CONCLUSIONS: The results suggest that culture of germinal vesicle and metaphase I oocytes in the presence of cumulus cells does not improve rates of IVM. In general, the process of rescue IVM does not appear to alter the frequency of oocytes with a normal chromosome copy number.
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Segregación Cromosómica , Técnicas de Maduración In Vitro de los Oocitos , Humanos , Adulto Joven , Adulto , Estudios Prospectivos , Oocitos , MeiosisRESUMEN
OBJECTIVE: To test for differences in recovery of lower urinary tract symptoms (LUTS) between patients with storage-positive vs -negative symptoms after laser enucleation of the prostate (LEP). PATIENTS AND METHODS: Consecutive storage-positive (severe storage symptoms, International Prostate Symptom Score [IPSS] storage subscore >8) vs storage-negative patients treated with LEP (November 2017-September 2022) within our tertiary-care database were identified. Mixed linear models tested for changes in IPSS and quality of life (QoL) at 1, 3 and 12 months after LEP. Multiple linear regression models tested for LUTS and QoL recovery risk factors at 1, 3 and 12 months. RESULTS: Of 291 study patients, 180 (62%) had storage-positive symptoms. There were no differences between storage-positive and -negative patients in mean adjusted total IPSS, IPSS-storage, IPSS-voiding and QoL at 12 months after LEP. In multiple linear regression models, storage-positive status was identified as a risk factor for higher IPSS at 1 month (ß coefficient 2.98, P = 0.004) and 3 months (ß coefficient 2.24, P = 0.04), as well as for more unfavourable QoL at 1 month (ß coefficient 0.74, P = 0.006) and 3 months (ß coefficient 0.73, P = 0.004) after LEP. Conversely, at 12 months there were no differences between storage-positive vs -negative patients. CONCLUSION: Storage-positive patients appear to experience similar long-term benefits from LEP compared to storage-negative patients. However, significant storage symptoms are associated with higher total IPSS and less favourable QoL at 1 and 3 months after LEP. These findings advocate for the consideration of LEP also in storage-positive cases with the need for thorough patient education especially in the initial post-LEP period.
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Conventional chemotherapies can stimulate the immune system by increasing tumour antigenicity (e.g., neoantigen exposure to immune cells) and altering adjuvanticity in the tumour (e.g., danger associated molecular patterns and cytokines). These molecules promote the recruitment, activation, and maturation of dendritic cells, which in turn, prime and activate cytotoxic T cells against tumour cells. However, several factors can decrease the immunostimulatory efficacy of chemotherapeutic agents. These include reduced tumour cell antigenicity and adjuvanticity and compromised immune function at a local and systemic level. Findings from preclinical studies show that dietary restriction and exercise promote systemic changes that may help to restore immune system function through several mechanisms, including an enhanced infiltration and function of antitumoral immune cells and a decrease in immunosuppressive cells, leading to a reduction in tumour volume. In addition, dietary restriction and exercise training in mice have been shown to enhance the efficacy of chemotherapy. In human studies there is also emerging evidence that dietary restriction and exercise can impact the immune system towards a more antitumoral profile. In this review, we discuss the immunostimulatory effects of dietary restriction (caloric restriction and fasting) and exercise training in preclinical cancer models, and potential synergies with chemotherapy. We then review clinical studies assessing the effects of these interventions on immune-related endpoints and tumour responses. Finally, we propose that combining dietary restriction with exercise could be a promising strategy to increase chemotherapy efficacy.
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Restricción Calórica , Neoplasias , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Animales , Ejercicio Físico/fisiología , Antineoplásicos/uso terapéutico , Terapia Combinada , Ratones , Terapia por Ejercicio/métodosRESUMEN
OBJECTIVES: To identify low cancer-specific mortality (CSM) risk lymph node-positive (pN1) radical prostatectomy (RP) patients. METHODS: Within Surveillance, Epidemiology and End Results database (2010-2015) pN1 RP patients were identified. Kaplan-Meier plots and multivariable Cox-regression (MCR) models were used. Pathological characteristics were used to identify patients at lowest CSM risk. RESULTS: Overall, 2197 pN1 RP patients were identified. Overall, 5-year cancer-specific survival (CSS) rate was 93.3%. In MCR models ISUP GG1-2 (hazard ratio [HR]: 0.12, p < 0.001), GG3 (HR: 0.14, p < 0.001), GG4 (HR: 0.35, p = 0.002), pT2 (HR: 0.27, p = 0.012), pT3a (HR: 0.28, p = 0.003), pT3b (HR: 0.39, p = 0.009), and 1-2 positive lymph nodes (HR: 0.64, p = 0.04) independently predicted lower CSM. Pathological characteristics subgroups with the most protective hazard ratios were used to identify low-risk (ISUP GG1-3 and pT2-3a and 1-2 positive lymph nodes) patients versus others (ISUP GG4-5 or pT3b-4 or ≥3 positive lymph nodes). In Kaplan-Meier analyses, 5-year CSS rates were 99.3% for low-risk (n = 480, 21.8%) versus 91.8% (p < 0.001) for others (n = 1717, 78.2%). CONCLUSIONS: Lymph node-positive RP patients exhibit variable CSS rates. Within this heterogeneous group, those at very low risk of CSM may be identified based on pathological characteristics, namely ISUP GG1-3, pT2-3a, and 1-2 positive lymph nodes. Such stratification scheme might be of value for individual patients counseling, as well as in design of clinical trials.
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Ganglios Linfáticos , Metástasis Linfática , Prostatectomía , Neoplasias de la Próstata , Programa de VERF , Humanos , Masculino , Prostatectomía/mortalidad , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/mortalidad , Persona de Mediana Edad , Anciano , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Tasa de Supervivencia , Estimación de Kaplan-Meier , Estudios de Seguimiento , Escisión del Ganglio Linfático/mortalidadRESUMEN
BACKGROUND: In 2021, the International Germ Cell Cancer Collaborative Group (IGCCCG) Update Consortium reported improved overall survival (OS) rates in a modern cohort of metastatic non-seminoma testis cancer patients within each of the IGCCCG prognosis groups (96% in good vs. 89% in intermediate vs. 67% in poor), compared to the previous IGCCCG publication (92% in good vs. 80% in intermediate vs. 48% in poor). We hypothesized that a similar survival improvement may apply to a contemporary North-American population-based cohort of non-seminoma testis cancer patients. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (2010-2018) was used. Kaplan-Meier plots and multivariable Cox regression models tested the effect of IGCCCG prognosis groups on overall mortality (OM). RESULTS: Of 1672 surgically treated metastatic non-seminoma patients, 778 (47%) exhibited good vs. 251 (15%) intermediate vs. 643 (38%) poor prognosis. In the overall cohort, five-year OS rate was 94% for good prognosis vs. 87% for intermediate prognosis vs. 65% for poor prognosis. In multivariable Cox regression models predicting OM, intermediate (Hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.4-3.9, P < 0.001) and poor prognosis group (HR 6.6, 95% CI 1.0-1.0, P < 0.001) were independent predictors of higher OM, relative to good prognosis group. CONCLUSIONS: The survival improvement reported by the IGCCCG Update Consortium is also operational in non-seminoma testis cancer patients within the most contemporary SEER database. This observation indicates that the survival improvement is not only applicable to centres of excellence, but also applies to other institutions at large.
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Programa de VERF , Neoplasias Testiculares , Humanos , Masculino , Neoplasias Testiculares/mortalidad , Neoplasias Testiculares/patología , Adulto , Pronóstico , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/mortalidad , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/terapia , Tasa de Supervivencia , Adulto Joven , Metástasis de la NeoplasiaRESUMEN
Understanding affective perceptual processes can further contribute to the explanation of motivation and actions, as well as sexual risk behaviors. Pornography can be considered salient emotional content and is popular, also among females. Yet, the female perspective on pornography has often been overlooked and it remains unclear how individual variables may be associated with the affective perception of pornography and could provide a risk profile. Possible associations between several sexual and psychological intrapersonal variables and the affective perception of various forms of pornography were analyzed from the female perspective. A sample of 231 females (M = 21.87 years; SD = 3.9 years) provided ratings of affective valence, arousal, disgust, and moral and ethical acceptance for mainstream pornographic and paraphilic images of dominance, submission, or sexual violence. Paraphilic pornography was perceived as less pleasant, arousing, and moral and ethically acceptable, but more disgusting compared to mainstream pornography. This was more pronounced among females who had never consumed pornography. Results further suggest that the female affective perception of pornography was associated with the following sexual intrapersonal variables: sexual sensation seeking for physical sensations, erotophilia, lack of sexual control, problematic pornography consumption, and sexual disgust sensitivity. Of the assessed psychological intrapersonal variables, only anxiety was negatively associated with disgust for paraphilic pornography. It is important to further analyze the female affective perception of pornography and associated variables to include them in strategies for prevention and for addressing problematic consequences of the acceptance of specific sexual content and behaviors, especially related to sexualized violence.
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Literatura Erótica , Conducta Sexual , Humanos , Femenino , Literatura Erótica/psicología , Conducta Sexual/psicología , Motivación , Emociones , PercepciónRESUMEN
The objective of this study was to establish the accuracy of the resting calcaneal stance position (RCSP) for the assessment of flat foot (FF) in children, aligned to the validity of the foot posture index (FPI). The RCSP cut-off point was explored, in context of both FF prevalence and the relationship between FF and body weight. A total of 205 healthy children, aged 5 to 10 years, participated in a cross-sectional study. Correlation was performed between RCSP and FPI. ROC curve technique was calculated to assess differentiation between groups. A score equal to or greater than 7 on the FPI was used as the 'gold standard' for analysis. The correlation between FPI and RCSP was significant (r = 0.63; p < 0.01). The discrimination score on the ROC curve (6 points/degrees) shows that the model can be used to identify FF through RCSP, with a sensitivity of 67% and specificity of 85% returned. Conclusion: The results of this study indicate the role of RCSP for simple, accessible and quick screening of paediatric FF. This is especially pertinent for non-podiatric healthcare professional without specialised paediatric foot knowledge. What is Known: ⢠Most children develop a normal arch quickly, and flat feet usually resolve on their own between 2 and 6 years of age. ⢠The measurement used to diagnose flat foot in children must be accurate, consistent, and valid to characterize the standard foot position. The Resting Calcaneal Stance Position (RCSP) is another widely used measure to evaluate the position of the flat foot in children. What is New: ⢠The RCSP cut-off point 6 shows a sensitivity of 67% and a specificity of 85% thanks to the FPI as the Gold standard. ⢠The RCSP is useful for health professionals who are not specialised in pediatric foot health. The RCSP is useful to detect flat foot in children.
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Pie Plano , Niño , Humanos , Preescolar , Pie Plano/diagnóstico , Estudios Transversales , Pie , Postura , Peso CorporalRESUMEN
This study aimed to investigate the variations in foot type, laxity, dynamic characteristics of gait, and the characteristics of the stance phase of gait, in relation to body mass index (BMI) and groups of children of different ages. Additionally, it aimed to explore the correlations between BMI and these variables across children groups of different ages. A cross-sectional study was conducted involving 196 infants aged between 5 and 10 years old. The variables assessed included BMI, foot type, laxity, dynamic variables, and characteristics of the stance phase of gait. Significant variations were observed in foot type, laxity, certain dynamic variables, and characteristics of the stance phase of gait between normoweight (NW) and overweight/obese (OW/OB) groups among children aged between 5 and 10 years old (p ranged between 0.019 and 0.050). Moreover, BMI was also positively associated with the initial forefoot contact, heel off, total duration of the step, and forefoot contact phase of children 7 to 10 years of age (p ranged between < 0.010 and 0.040). Conclusion: Children who are OW/OB had alterations at different stages of gait. Being OW/OB is related to alterations of the phases of gait mainly from 7 to 10 years of age, and spending more time in each of the phases of walking. This could indicate that children who are OW/OB, in addition to walking slower, overload the musculoskeletal system, subjecting their joints and muscles to greater stress. What is Known: ⢠Children who are overweight (OW) and obese (OB) can experience changes in their musculoskeletal systems, posture, and gait due to increased body mass index. ⢠OW and OB children experience additional stress on their musculoskeletal systems, impacting posture, biomechanics, mobility, physical activity, and daily tasks. Excessive plantar loading is linked to foot pain in adults. What is New: ⢠Body mass index was positively associated with initial forefoot contact, heel off, total duration of the step, and forefoot contact phase in children aged 7 to 10 years old. OW/OB children aged 5-6 exhibited less ankle dorsiflexion and smaller relaxed calcaneal stance position (RCSP) as compared to normal-weight children. ⢠Obese children aged 5-6 showed less pronation excursion, suggesting altered frontal plane movement due to RCSP differences. Children aged 7-8 who are OW/OB spent more time in certain gait phases, particularly in the forefoot contact phase. Being OW/OB is linked to altered gait parameters such as initial forefoot, heel off, total step duration, and forefoot contact phase. Being OW/OB was associated with a longer forefoot contact phase, particularly in the right foot.
Asunto(s)
Obesidad Infantil , Adulto , Lactante , Niño , Humanos , Preescolar , Recién Nacido , Estudios Transversales , Sobrepeso , Marcha/fisiología , Pie/fisiología , Fenómenos BiomecánicosRESUMEN
INTRODUCTION: Childhood trauma and adversities (CTA) and aberrant salience (AS) have a pivotal role in schizophrenia development, but their interplay with psychotic symptoms remains vague. We explored the mediation performed by AS between CTA and psychotic symptomatology in schizophrenia. METHODS: We approached 241 adults suffering from schizophrenia spectrum disorders (SSDs), who have been in the unit for at least 12 consecutive months, excluding the diagnosis of dementia, and recent substance abuse disorder, and cross-sectional evaluated through the Aberrant Salience Inventory (ASI), Childhood Trauma Questionnaire Short-Form (CTQ-SF), and Positive and Negative Symptom Scale (PANSS). We tested a path-diagram where AS mediated the relationship between CTA and psychosis, after verifying each measure one-dimensionality through confirmatory factor analysis. RESULTS: The final sample comprised 222 patients (36.9% female), with a mean age of 42.4 (± 13.3) years and an average antipsychotic dose of 453.6 (± 184.2) mg/day (chlorpromazine equivalents). The mean duration of untreated psychosis was 1.8 (± 2.0) years while the mean onset age was 23.9 (± 8.2) years. Significant paths were found from emotional abuse to ASI total score (ß = 0.39; p < .001) and from ASI total score to PANSS positive (ß = 0.17; p = .019). Finally, a statistically significant indirect association was found from emotional abuse to PANSS positive mediated by ASI total score (ß = 0.06; p = .041; CI 95% [0.01, 0.13]). CONCLUSION: Emotional abuse has an AS-mediated effect on positive psychotic symptomatology. AS evaluation could allow a better characterization of psychosis as well as explain the presence of positive symptoms in adults with SSDs who experienced CTA.