RESUMEN
BACKGROUND: Melanoma is increasingly recognized as a heterogeneous disease, with conflicting evidence regarding whether cutaneous head and neck melanoma (CHNM) represents a distinct entity. OBJECTIVE: Comparison of clinicopathological features and treatment outcomes of CHNM and cutaneous melanomas of other sites (CMOS). METHODS: Patients with CHNM and CMOS diagnosed between 2000-2018 were included. Locoregional control (LRC), distant metastasis-free survival (DMFS), melanoma-specific survival (MSS), and overall survival (OS) were described using the Kaplan-Meier method. Cox regression analyses were performed to examine associations between prognostic factors and outcomes. Additional analyses of survival from time of stage IV disease diagnosis were undertaken, stratified by receipt of BRAF-targeted therapy and immune checkpoint inhibitor (ICI) immunotherapy. RESULTS: Of 3007 CHNM and 10637 CMOS patients, CHNM had more adverse pathological features (median age 65.9 vs. 58.5, p<0.001, median Breslow thickness 1.7mm vs. 1.2mm, p<0.001, ulceration 21.2% vs. 18.2%, p<0.001). CHNM had worse LRC (HR 1.17, p<0.001) and DMFS (HR 1.25, p<0.001) but there were no significant differences in MSS or OS. Amongst stage IV patients who received ICI, CHNM had better MSS (HR 0.56, p=0.001) and OS (HR 0.57, p<0.001) on multivariable analyses. LIMITATIONS: Retrospective study, offset by prospective data collection. CONCLUSION: CHNM is associated with a distinct clinicopathological and prognostic profile.
RESUMEN
Peroxiporins are a specialized subset of aquaporins, which are integral membrane proteins primarily known for facilitating water transport across cell membranes. In addition to the classical water transport function, peroxiporins have the unique capability to transport hydrogen peroxide (H2O2), a reactive oxygen species involved in various cellular signaling pathways and regulation of oxidative stress responses. The regulation of H2O2 levels is crucial for maintaining cellular homeostasis, and peroxiporins play a significant role in this process by modulating its intracellular and extracellular concentrations. This ability to facilitate the passage of H2O2 positions peroxiporins as key players in redox biology and cellular signaling, with implications for understanding and treating various diseases linked to oxidative stress and inflammation. This review provides updated information on the physiological roles of peroxiporins and their implications in disease, emphasizing their potential as novel biomarkers and drug targets in conditions where they are dysregulated, such as inflammation and cancer.
Asunto(s)
Acuaporinas , Inflamación , Neoplasias , Estrés Oxidativo , Humanos , Inflamación/metabolismo , Neoplasias/metabolismo , Animales , Acuaporinas/metabolismo , Peróxido de Hidrógeno/metabolismo , Transducción de Señal , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Neurodegenerative diseases (NDDs) are an increasing group of chronic and progressive neurological disorders that ultimately lead to neuronal cell failure and death. Despite all efforts throughout decades, their burden on individuals and society still casts one of the most massive socioeconomic problems worldwide. The neuronal failure observed in NDDs results from an intricacy of events, mirroring disease complexity, ranging from protein aggregation, oxidative stress, (neuro)inflammation, and even blood-brain barrier (BBB) dysfunction, ultimately leading to cognitive and motor symptoms in patients. As a result of such complex pathobiology, to date, there are still no effective treatments to treat/halt NDDs progression. Fortunately, interest in the bioavailable low molecular weight (LMW) phenolic metabolites derived from the metabolism of dietary (poly)phenols has been rising due to their multitargeted potential in attenuating multiple NDDs hallmarks. Even if not highly BBB permeant, their relatively high concentrations in the bloodstream arising from the intake of (poly)phenol-rich diets make them ideal candidates to act within the vasculature and particularly at the level of BBB. In this review, we highlight the most recent - though still scarce - studies demonstrating LMW phenolic metabolites' ability to modulate BBB homeostasis, including the improvement of tight and adherens junctional proteins, as well as their power to decrease pro-inflammatory cytokine secretion and oxidative stress levels in vitro and in vivo. Specific BBB-permeant LMW phenolic metabolites, such as simple phenolic sulfates, have been emerging as strong BBB properties boosters, pleiotropic compounds capable of improving cell fitness under oxidative and pro-inflammatory conditions. Nevertheless, further studies should be pursued to obtain a holistic overview of the promising role of LMW phenolic metabolites in NDDs prevention and management to fully harness their true therapeutic potential.
Asunto(s)
Barrera Hematoencefálica , Polifenoles , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Humanos , Animales , Polifenoles/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Peso Molecular , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/metabolismo , Fenoles/metabolismo , Fenoles/farmacología , Estrés Oxidativo/fisiología , Estrés Oxidativo/efectos de los fármacosRESUMEN
Silk proteins have been highlighted in the past decade for tissue engineering (TE) and skin regeneration due to their biocompatibility, biodegradability, and exceptional mechanical properties. While silk fibroin (SF) has high structural and mechanical stability with high potential as an external protective layer, traditionally discarded sericin (SS) has shown great potential as a natural-based hydrogel, promoting cell-cell interactions, making it an ideal material for direct wound contact. In this context, the present study proposes a new wound dressing approach by developing an SS/SF bilayer construct for full-thickness exudative wounds. The processing methodology implemented included an innovation element and the cryopreservation of the SS intrinsic secondary structure, followed by rehydration to produce a hydrogel layer, which was integrated with a salt-leached SF scaffold to produce a bilayer structure. In addition, a sterilization protocol was developed using supercritical technology (sCO2) to allow an industrial scale-up. The resulting bilayer material presented high porosity (>85%) and interconnectivity while promoting cell adhesion, proliferation, and infiltration of human dermal fibroblasts (HDFs). SS and SF exhibit distinct secondary structures, pore sizes, and swelling properties, opening new possibilities for dual-phased systems that accommodate the different needs of a wound during the healing process. The innovative SS hydrogel layer highlights the transformative potential of the proposed bilayer system for biomedical therapeutics and TE, offering insights into novel wound dressing fabrication.
RESUMEN
Microbial contamination poses a threat to both the preservation of library and archival collections and the health of staff and users. This study investigated the microbial communities and potential health risks associated with the UNESCO-classified Norwegian Sea Trade Archive (NST Archive) collection exhibiting visible microbial colonization and staff health concerns. Dust samples from book surfaces and the storage environment were analysed using culturing methods, qPCR, Next Generation Sequencing, and mycotoxin, cytotoxicity, and azole resistance assays. Penicillium sp., Aspergillus sp., and Cladosporium sp. were the most common fungi identified, with some potentially toxic species like Stachybotrys sp., Toxicladosporium sp., and Aspergillus section Fumigati. Fungal resistance to azoles was not detected. Only one mycotoxin, sterigmatocystin, was found in a heavily contaminated book. Dust extracts from books exhibited moderate to high cytotoxicity on human lung cells, suggesting a potential respiratory risk. The collection had higher contamination levels compared to the storage environment, likely due to improved storage conditions. Even though overall low contamination levels were obtained, these might be underestimated due to the presence of salt (from cod preservation) that could have interfered with the analyses. This study underlines the importance of monitoring microbial communities and implementing proper storage measures to safeguard cultural heritage and staff well-being.
RESUMEN
Many mechanisms underlying an effective immunotherapy-induced antitumour response are transient and critically time dependent. This is equally true for several immunological events in the tumour microenvironment induced by other cancer treatments. Immune checkpoint therapy (ICT) has proven to be very effective in the treatment of some cancers, but unfortunately, with many cancer types, most patients do not experience a benefit. To improve outcomes, a multitude of clinical trials are testing combinations of ICT with various other treatment modalities. Ideally, those combination treatments should take time-dependent immunological events into account. Recent studies have started to map the dynamic cellular and molecular changes that occur during treatment with ICT, in the tumour and systemically. Here, we overlay the dynamic ICT response with the therapeutic response following surgery, radiotherapy, chemotherapy and targeted therapies. We propose that by combining treatments in a time-conscious manner, we may optimally exploit the interactions between the individual therapies.
Asunto(s)
Inmunoterapia , Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Factores de Tiempo , Terapia Combinada , AnimalesRESUMEN
Heterogeneous resistance to immunotherapy remains a major challenge in cancer treatment, often leading to disease progression and death. Using CITE-seq and matched 40-plex PhenoCycler tissue imaging, we performed longitudinal multimodal single-cell analysis of tumors from metastatic melanoma patients with innate resistance, acquired resistance, or response to immunotherapy. We established the multimodal integration toolkit to align transcriptomic features, cellular epitopes, and spatial information to provide deeper insights into the tumors. With longitudinal analysis, we identified an "immune-striving" tumor microenvironment marked by peri-tumor lymphoid aggregates and low infiltration of T cells in the tumor and the emergence of MITF+SPARCL1+ and CENPF+ melanoma subclones after therapy. The enrichment of B cell-associated signatures in the molecular composition of lymphoid aggregates was associated with better survival. These findings provide further insights into the establishment of microenvironmental cell interactions and molecular composition of spatial structures that could inform therapeutic intervention.
Asunto(s)
Resistencia a Antineoplásicos , Inmunoterapia , Melanoma , Análisis de la Célula Individual , Microambiente Tumoral , Microambiente Tumoral/inmunología , Humanos , Inmunoterapia/métodos , Melanoma/terapia , Melanoma/inmunología , Melanoma/patología , MultiómicaRESUMEN
Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy. In NSCLC, the impact of the distribution of metastatic sites and the response to systemic therapy combinations remain poorly understood. In a retrospective cohort study of patients with unresectable stage III/IV NSCLC who received first-line systemic therapy, we sought to assess the association between the site of metastases with patterns of response and progression. Data regarding demographics, tumour characteristics (including site, size, and volume of metastases), treatment, and outcomes were examined at two cancer care centres. The endpoints included organ site-specific response rate, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Two-hundred and eighty-five patients were included in the analysis. In a multivariate analysis, patients with bone metastases had a reduced ORR, PFS, and OS. Primary resistance was also more likely in patients with bone metastases. Patients with bone or liver metastases had a shorter OS when receiving ICIs with or without chemotherapy, but not with chemotherapy alone, suggesting an immunological basis for therapeutic resistance. A directed assessment of the tumour microenvironment in these locations and a deeper understanding of the drivers of organ-specific resistance to immunotherapy are critical to optimise novel combination therapies and sequencing in these patients.
RESUMEN
BACKGROUND: Seminal trials with first-line pembrolizumab for metastatic non-small cell lung cancer (NSCLC) mandated a maximum two-years treatment. We describe real-world outcomes of a multi-site Australian cohort of patients who completed two-years of pembrolizumab. METHODS: Retrospective data were collected from the national AUstralian Registry and biObank of thoRacic cAncers (AURORA). Primary endpoints were progression rate post pembrolizumab discontinuation; and progression free survival (PFS). Local treatment of oligoprogressive disease during pembrolizumab was allowed. RESULTS: A total of 71 patients from six centers, median age 66.0 years, 49% male and 90% ECOG ≤ 1 were identified. Patients were Caucasian (82%) or Asian (16%); past (66%) or current (24%) smokers with mean 37 pack-years. Histology comprised 73% adenocarcinoma and 16% squamous. 18 patients (25%) had brain metastases at diagnosis. Median PD-L1 tumor proportion score (TPS) was 68%; 12 patients (17%) TPS < 1% and 43 (61%) TPS ≥ 50%. No patients had EGFR/ALK/ROS1 alterations; 29/49 tested (60%) had KRAS mutations. Median follow up was 38.7 months. Objective response rate 78.6%. Median PFS 46.1 months (95% CI 39.5-NR), not reached (46.1-NR) in PD-L1 TPS ≥ 1% versus 28.1 months (16.3-NR) in TPS < 1% (P = .013). 17 patients (24%) received additional local therapy for oligoprogression. Post pembrolizumab discontinuation, 20 patients (28%) had disease progression. Higher rates of progression occurred with TPS < 1% (OR 3.46, P = .06), without complete response (OR 5.06, P = .04), and with treated oligoprogression (OR 3.11, P = .05). 36-month landmark survival was 98.2%. CONCLUSION: Patients completing two-years of pembrolizumab for NSCLC in an Australian cohort had high rates of KRAS mutation and PD-L1 expression; a proportion had brain metastases and treated oligoprogression. Progression post pembrolizumab was higher in PD-L1 TPS < 1% and in those without complete response.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Masculino , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Antineoplásicos Inmunológicos/uso terapéutico , Australia , Anciano de 80 o más Años , Estudios de Seguimiento , Tasa de Supervivencia , Adulto , Resultado del TratamientoRESUMEN
BACKGROUND: The combination of anti-PD-1 and anti-CTLA-4 has been associated with improvement in response and survival over anti-PD-1 monotherapy in unselected patients with advanced melanoma. Whether patients with liver metastases also benefit from the combination of anti-PD-1 and anti-CTLA-4 over anti-PD-1, is unclear. In this study, we sought to assess whether the combination of anti-PD-1 and anti-CTLA-4 leads to better response, progression-free survival and overall survival, compared with anti-PD-1 monotherapy for patients with liver metastases. METHODS: We have conducted an international multicentre retrospective study. Patients with advanced melanoma with liver metastases treated with 1st line anti-PD1 monotherapy or with anti-CTLA-4 were included. The endpoints of this study were: objective response rate, progression-free survival and overall survival. RESULTS: With a median follow-up from commencement of anti-PD-1 monotherapy or in combination with anti-CTLA-4 of 47 months (95% CI, 42-51), objective response rate was higher with combination therapy (47%) versus anti-PD-1 monotherapy (35%) (p = 0.0027), while progression-free survival and overall survival were not statistically different between both treatment groups. However, on multivariable analysis with multiple imputation for missing values and adjusting for predefined variables, combination of anti-PD1 and anti-CTLA-4 was associated with higher objective response (OR 2.21, 1.46 - 3.36; p < 0.001), progression-free survival (HR 0.73, 0.57 - 0.92; p = 0.009) and overall survival (HR 0.71, 0.54 - 0.94; p = 0.018) compared to anti-PD1 monotherapy. CONCLUSIONS: Findings from this study will help guide treatment selection for patients who present with liver metastases, suggesting that combination therapy should be considered for this group of patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno CTLA-4 , Inhibidores de Puntos de Control Inmunológico , Neoplasias Hepáticas , Melanoma , Receptor de Muerte Celular Programada 1 , Humanos , Melanoma/tratamiento farmacológico , Melanoma/secundario , Melanoma/mortalidad , Masculino , Estudios Retrospectivos , Femenino , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/mortalidad , Persona de Mediana Edad , Antígeno CTLA-4/antagonistas & inhibidores , Anciano , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Supervivencia sin Progresión , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/mortalidadRESUMEN
BACKGROUND: Hemin is clinically used in acute attacks of porphyria; however, recent evidence has also highlighted its capability to stimulate the heme oxygenase enzyme, being associated with cytoprotective, antioxidant, and anti-inflammatory effects. Indeed, current preclinical evidence emphasizes the potential anti-inflammatory role of hemin through its use in animal models of disease. Nevertheless, there is no consensus about the underlying mechanism(s) and the most optimal therapeutic regimens. Therefore, this review aims to summarize, analyze, and discuss the current preclinical evidence concerning the pharmacological effect of hemin. METHODS: Following the application of the search expression and the retrieval of the articles, only nonclinical studies in vivo written in English were considered, where the potential anti-inflammatory effect of hemin was evaluated. RESULTS: Forty-nine articles were included according to the eligibility criteria established. The results obtained show the preference of using 30 to 50 mg/kg of hemin, administered intraperitoneally, in both acute and chronic contexts. This drug demonstrates significant anti-inflammatory and antioxidant activities considering its capacity for reducing the expression of proinflammatory and oxidative markers. CONCLUSIONS: This review highlighted the significant anti-inflammatory and antioxidant effects of hemin, providing a clearer vision for the medical community about the use of this drug in several human diseases.
RESUMEN
Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disorder which may affect the gastrointestinal system. Half of the patients with SLE experience gastrointestinal symptoms, with the most common being nausea, vomiting, anorexia, and abdominal pain. Mesenteric vasculitis is a severe and rare complication of SLE and one of the most frequent causes of severe acute abdominal pain. The authors present a case of a 57-year-old woman with SLE who was diagnosed with necrotizing mesenteric vasculitis following a urinary septic shock. The patient was treated with high-dose corticosteroid therapy and cyclophosphamide, with resolution of the clinical picture.
Asunto(s)
Enfermedades Gastrointestinales , Lupus Eritematoso Sistémico , Lesiones del Sistema Vascular , Vasculitis , Femenino , Humanos , Persona de Mediana Edad , Lupus Eritematoso Sistémico/complicaciones , Vasculitis/complicaciones , Enfermedades Gastrointestinales/complicaciones , Ciclofosfamida/uso terapéutico , Dolor Abdominal/complicaciones , Lesiones del Sistema Vascular/complicacionesRESUMEN
OBJECTIVES: We aim to independently assess the validity of the damage index for antiphospholipid syndrome (DIAPS) in thrombotic antiphospholipid syndrome (APS) patients by exploring the prevalence and risk factors of organ damage and evaluating its impact on health-related quality of life (HR-QoL). METHODS: Cross-sectional study including all thrombotic APS patients (Sydney criteria) attending a Portuguese tertiary centre. Damage was assessed using the DIAPS, and HR-QoL using the 3- and 5-level EuroQol HR-QoL (EQ-D5-3L and 5L), and Visual Analogue Scale (VAS) applied via a phone questionnaire. Spearman's correlation between DIAPS and the HR-QoL scales was performed. Risk factors for damage accrual and HR-QoL impairment were explored using univariate and multivariate logistic regression. RESULTS: Among the 108 patients (female, 65.7%; white, 90.7%; primary APS, 75.9%; median disease duration, 6 years), damage (DIAPS≥1) developed in 48.2% of patients (mean ± SD DIAPS, 3.08 ± 1.83). DIAPS's neuropsychiatric domain was the most affected (24.2%), followed by the peripheral vascular domain (20.3%). No clinical, demographic nor laboratory parameters were significantly associated with damage. Regarding HR-QoL, pain/discomfort, anxiety/depression and usual activities domains were the most frequently impaired in both scales. DIAPS's domains correlated similarly with the EQ-5D-3L and 5L scales' individual domains. Female sex, medical disorders, secondary APS and type of presenting thrombosis (arterial) increased the risk of HR-QoL impairment. Total DIAPS was associated with higher odds of mobility, self-care and pain/discomfort impairment in both EQ-5D-3L and 5L scales but lost its independent risk in multivariable analysis. CONCLUSION: This external validation of DIAPS reinforces the ability of the score to correlate with HR-QoL while also highlighting risk factors for HR-QoL impairment other than damage accrual.
Asunto(s)
Síndrome Antifosfolípido , Calidad de Vida , Trombosis , Humanos , Síndrome Antifosfolípido/complicaciones , Femenino , Masculino , Adulto , Estudios Transversales , Persona de Mediana Edad , Factores de Riesgo , Trombosis/etiología , Encuestas y Cuestionarios , Portugal/epidemiología , Índice de Severidad de la Enfermedad , Modelos LogísticosRESUMEN
The biological underpinnings of therapeutic resistance to immune checkpoint inhibitors (ICI) in adolescent and young adult (AYA) melanoma patients are incompletely understood. Here, we characterize the immunogenomic profile and spatial architecture of the tumor microenvironment (TME) in AYA (aged ≤ 30 years) and older adult (aged 31-84 years) patients with melanoma, to determine the AYA-specific features associated with ICI treatment outcomes. We identify two ICI-resistant spatiotypes in AYA patients with melanoma showing stroma-infiltrating lymphocytes (SILs) that are distinct from the adult TME. The SILhigh subtype was enriched in regulatory T cells in the peritumoral space and showed upregulated expression of immune checkpoint molecules, while the SILlow subtype showed a lack of immune activation. We establish a young immunosuppressive melanoma score that can predict ICI responsiveness in AYA patients and propose personalized therapeutic strategies for the ICI-resistant subgroups. These findings highlight the distinct immunogenomic profile of AYA patients, and individualized TME features in ICI-resistant AYA melanoma that require patient-specific treatment strategies.
Asunto(s)
Melanoma , Humanos , Adolescente , Adulto Joven , Anciano , Melanoma/terapia , Inmunoterapia , Linfocitos T Reguladores , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Proteínas de Punto de Control Inmunitario , Microambiente TumoralRESUMEN
Introduction: An increasing aggressiveness in cancer treatment at the end of life (EoL) has been reported in several, but not all, countries. This study aimed to see how aggressive cancer treatment is at the EoL in an oncology center. Methods: Retrospective study of patients 18 years or older with a solid cancer diagnosis who died in 2017. The focus was systemic anticancer therapy (SACT), excluding hormonotherapy. Results: In 2017, 2024 patients with solid tumors died. Of those patients, 1262 (62%) were male, and the median age was 69 (range 19-97) years. The most frequent primary cancer was lung cancer, followed by colorectal and stomach cancers, and 740 (37%) patients had metastatic disease. The median interval between SACT and death was 61 days. Of the patients undergoing SACT, 216 (27%) did it in the last month of life, 174 (22%) between 8 and 30 days from death, and 42 (5%) in the last week. On multivariable analysis, head and neck, colorectal, breast, and melanoma primaries; age group (older than 65 years); and metastatic disease had statistical significance associated with SACT. Of these variables, only metastatic disease is more likely to undergo SACT. Conclusion: This study confirms the relatively frequent aggressiveness in cancer treatment at the EoL. Taking into consideration previously published data, it can be tentatively concluded that the use of SACT increased in the last month and the last week of life.
RESUMEN
Aquaporin-3 (AQP3) is a membrane channel with dual aquaglyceroporin/peroxiporin activity, facilitating the diffusion of water, glycerol and H2O2 across cell membranes. AQP3 shows aberrant expression in melanoma and its role in cell adhesion, migration and proliferation is well described. Gold compounds were shown to modulate AQP3 activity with reduced associated toxicity, making them promising molecules for cancer therapy. In this study, we validated the phenotype resulting from AQP3-silencing of two melanoma cell lines, MNT-1 and A375, which resulted in decreased H2O2 permeability. Subsequently, the AQP3 inhibitory effect of a new series of organogold compounds derived from Auphen, a potent AQP3 inhibitor, was first evaluated in red blood cells (RBCs) that highly express AQP3, and then in HEK-293T cells with AQP3 overexpression to ascertain the compounds' specificity. The first screening in RBCs unveiled two organogold compounds as promising blockers of AQP3 permeability. Moderate reduction of glycerol permeability but drastic inhibition of H2O2 permeability was detected for some of the gold derivatives in both AQP3-overexpressing cells and human melanoma cell lines. Additionally, all compounds were effective in impairing cell adhesion, proliferation and migration, although in a cell type-dependent manner. In conclusion, our data show that AQP3 peroxiporin activity is crucial for melanoma progression and highlight organogold compounds as promising AQP3 inhibitors with implications in melanoma cell adhesion, proliferation and migration, unveiling their potential as anticancer drugs against AQP3-overexpressing tumours. KEY POINTS: AQP3 affects cellular redox balance. Gold compounds inhibit AQP3 permeability in melanoma cells. AQP3 is involved in cell adhesion, proliferation and migration of melanoma. Blockage of AQP3 peroxiporin activity impairs melanoma cell migration. Gold compounds are potential anticancer drug leads for AQP3-overexpressing cancers.
Asunto(s)
Acuaporina 3 , Adhesión Celular , Movimiento Celular , Proliferación Celular , Melanoma , Acuaporina 3/metabolismo , Acuaporina 3/genética , Humanos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/metabolismo , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Células HEK293 , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/farmacologíaRESUMEN
Introduction: Brain metastases commonly occur in patients with non-small cell lung cancer (NSCLC). Standard first-line treatment for NSCLC, without an EGFR, ALK or ROS1 mutation, is either chemoimmunotherapy or anti-PD-1 monotherapy. Traditionally, patients with symptomatic or untreated brain metastases were excluded from the pivotal clinical trials that established first-line treatment recommendations. The intracranial effectiveness of these treatment protocols has only recently been elucidated in small-scale prospective trials. Methods: Patients with NSCLC and brain metastases, treated with first-line chemoimmunotherapy or anti-PD-1 monotherapy were selected from the Australian Registry and biObank of thoracic cancers (AURORA) clinical database covering seven institutions. The primary outcome was a composite time-to-event (TTE) outcome, including extracranial and intracranial progression, death, or need for local intracranial therapy, which served as a surrogate for disease progression. The secondary outcome included overall survival (OS), intracranial objective response rate (iORR) and objective response rate (ORR). Results: 116 patients were included. 63% received combination chemoimmunotherapy and 37% received anti-PD-1 monotherapy. 69% of patients received upfront local therapy either with surgery, radiotherapy or both. The median TTE was 7.1 months (95% CI 5 - 9) with extracranial progression being the most common progression event. Neither type of systemic therapy or upfront local therapy were predictive of TTE in a multivariate analysis. The median OS was 17 months (95% CI 13-27). Treatment with chemoimmunotherapy was predictive of longer OS in multivariate analysis (HR 0.35; 95% CI 0.14 - 0.86; p=0.01). The iORR was 46.6%. The iORR was higher in patients treated with chemoimmunotherapy compared to immunotherapy (58% versus 31%, p=0.01). The use of chemoimmunotherapy being predictive of iORR in a multivariate analysis (OR 2.88; 95% CI 1.68 - 9.98; p=0.04). Conclusion: The results of this study of real-world data demonstrate the promising intracranial efficacy of chemoimmunotherapy in the first-line setting, potentially surpassing that of immunotherapy alone. No demonstrable difference in survival or TTE was seen between receipt of upfront local therapy. Prospective studies are required to assist clinical decision making regarding optimal sequencing of local and systemic therapies.
RESUMEN
Biosocial factors play a crucial role in the physical-motor development (PMD) of children during the preschool age. The present study aims to identify physical-motor profiles throughout preschool age (3-6 years) and explore associations between profiles and selected biosocial factors such as age, sex, prematurity, weight, height, BMI, and participation in extracurricular physical activities. Data from 412 typically developing children (46.6% girls and 53.4% boys), aged 35-71 months (M = 51.21, SD = 10.47) was collected using the Psychomotor Activities Checklist and specifically the scale of Psycho-Motor Aspects. Cluster analysis made it possible to define four different childhood PMD profiles. High PMD; High PMD except left laterality; medium-low PMD; and low PMD. High PMD profile includes older children, with anthropometric measurements closer to the WHO recommendations, fewer preterm children, and greater participation in extracurricular physical activities. Low PMD profile includes younger children, with weight slightly above and height slightly below the WHO recommendations and low participation in extracurricular physical activities. This study allows us to identify specific trends that may be decisive for the motor development of children throughout preschool age, highlighting selected biological variables and participation in extracurricular physical activities.
RESUMEN
BACKGROUND: Immune checkpoint inhibitors are frequently associated with the development of immunotherapy-related adverse events (irAEs). The exact etiology, including the role of environmental factors, remains incompletely understood. METHODS: We analyzed the records of 394 melanoma patients from three centers (northern and southern hemisphere). Patients had received at least one cycle of anti-PD-1/anti-CTLA-4 with a minimum follow-up of 3 months. We study the distribution and time to irAEs onset throughout the calendar year. RESULTS: 764 irAEs were recorded; the most frequent were skin rash (35%), hepatitis (32%) and colitis (30%). The irAEs incidence was the highest in autumn and winter, and the ratio for the 'number of irAEs' per 'therapies commenced' was the highest in winter and lowest in summer (2.4 and 1.7, respectively). Season-specific patterns in the time of irAEs onset were observed for pneumonitis (shorter time to onset in autumn, p = 0.025), hepatitis (shorter time to onset in spring, p = 0.016) and sarcoid-like immune reaction (shorter time to onset in autumn, p = 0.041). Season-specific patterns for early-onset irAEs were observed for hepatitis (spring, p = 0.023) and nephritis (summer, p = 0.017). Early-onset pneumonitis was more frequent in autumn-winter (p = 0.008) and early-onset nephritis in spring-summer (p = 0.004). CONCLUSIONS: Environmental factors that are associated with particular seasons may contribute to the development of certain irAEs and suggest the potential effect of environmental triggers. The identification of these factors may enhance preventive and therapeutic strategies to reduce the morbidity of irAEs.