RESUMEN
While the coronavirus disease-2019 (COVID-19) might have increased acute episodes in people living with sickle cell disease (SCD), it may also have changed their reliance on emergency department (ED) services. We assessed the impact of the COVID-19 pandemic and lockdowns on ED visits in adult SCD people followed in five French reference centres, with a special focus on 'high users' (≥10 visits in 2019). We analysed the rate of ED visits from 1 January 2015 to 31 December 2021, using a self-controlled case series. Among 1530 people (17 829 ED visits), we observed a significant reduction in ED visits during and after lockdowns, but the effect vanished over time. Compared to pre-pandemic, incidence rate ratios for ED visits were 0.59 [95% CI 0.52-0.67] for the first lockdown, 0.66 [95% CI 0.58-0.75] for the second and 0.85 [95% CI 0.73-0.99] for the third. High users (4% of people but 33.7% of visits) mainly drove the reductions after the first lockdown. COVID-19 lockdowns were associated with reduced ED visits. While most people returned to their baseline utilization by April 2021, high users had a lasting decrease in ED visits. Understanding the factors driving the drop in ED utilization among high users might inform clinical practice and health policy.
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Anemia de Células Falciformes , COVID-19 , Servicio de Urgencia en Hospital , SARS-CoV-2 , Humanos , COVID-19/epidemiología , Anemia de Células Falciformes/epidemiología , Anemia de Células Falciformes/terapia , Servicio de Urgencia en Hospital/estadística & datos numéricos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Francia/epidemiología , Pandemias , Estudios de Cohortes , Adulto Joven , Adolescente , Aceptación de la Atención de Salud/estadística & datos numéricosRESUMEN
BACKGROUND AND PURPOSE: Intracranial aneurysms are frequent in patients with sickle cell anemia, while subarachnoid hemorrhage is a major cause of death and disability in young adult patients. Several characteristics, such as younger age and smaller size at rupture, may incline therapeutic decision towards exclusion treatments. Clinical guidelines on treatment of unruptured intracranial aneurysms in this population are still missing. We aimed to assess the safety and efficacy of the treatment of unruptured intracranial aneurysm in patients with sickle cell anemia, using an adapted hematological preparation regimen. PATIENTS AND METHODS: Adult patients with sickle cell anemia and treated unruptured aneurysms by endovascular therapy or neurosurgery were included in this retrospective cohort study. Treatment decision was reached after multi-disciplinary assessment. A pre-operative blood transfusion protocol was undertaken targeting a HbS below 30%. Demographic data, hematological preparation parameters and clinical and radiological outcomes were documented. RESULTS AND CONCLUSIONS: Twenty-five procedures were performed in 18 patients encompassing 19 aneurysms treated by embolization and 6 by surgery. Median age at treatment was 34 years-old and median aneurysm dome size was 4.4 mm. Immediate aneurysm exclusion rate was 85.7% after endovascular therapy and 100% after neurosurgery. Median follow-up was 6 months, with all patients being asymptomatic at last follow-up. Two transitory ischemic neurological deficits, as well as four cases of iodine-induced encephalopathy were identified after embolization. No complication occurred after surgery. Endovascular therapy by coiling and neurosurgical treatment of unruptured intracranial aneurysms appears to be safe in patients with sickle cell anemia and should be considered given the specific hemorrhagic risk observed in this population. A rigorous hematological preparation, associated with a dedicated perioperative protocol and an adequate therapeutic strategy are essential prerequisites.
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Anemia de Células Falciformes , Aneurisma Roto , Embolización Terapéutica , Procedimientos Endovasculares , Aneurisma Intracraneal , Adulto Joven , Humanos , Adulto , Estudios de Cohortes , Aneurisma Intracraneal/complicaciones , Aneurisma Intracraneal/diagnóstico por imagen , Aneurisma Intracraneal/terapia , Estudios Retrospectivos , Resultado del Tratamiento , Procedimientos Endovasculares/métodos , Embolización Terapéutica/métodos , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/terapia , Aneurisma Roto/cirugíaRESUMEN
BACKGROUND: Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously. PATIENTS AND METHODS: Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer. RESULTS: In the OSP (n = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n = 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1∗28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1∗1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n = 1/11; 9.1% ORR). CONCLUSIONS: SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.
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Inmunoconjugados , Neoplasias Pulmonares , Anticuerpos Monoclonales Humanizados , Camptotecina/análogos & derivados , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Advanced recurrent ovarian cancer (ROC) is the leading cause of gynecologic cancer-related death in developed countries and new treatments are needed. Previous studies of immune checkpoint blockade showed low objective response rates (ORR) in ROC with no identified predictive biomarker. PATIENTS AND METHODS: This phase II study of pembrolizumab (NCT02674061) examined two patient cohorts with ROC: cohort A received one to three prior lines of treatment with a platinum-free interval (PFI) or treatment-free interval (TFI) between 3 and 12 months and cohort B received four to six prior lines with a PFI/TFI of ≥3 months. Pembrolizumab 200 mg was administered intravenously every 3 weeks until cancer progression, toxicity, or completion of 2 years. Primary end points were ORR by Response Evaluation Criteria in Solid Tumors version 1.1 per blinded independent central review by cohort and by PD-L1 expression measured as combined positive score (CPS). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Cohort A enrolled 285 patients; the first 100 served as the training set for PD-L1 biomarker analysis. Cohort B enrolled 91 patients. ORR was 7.4% for cohort A and 9.9% for cohort B. Median DOR was 8.2 months for cohort A and not reached for cohort B. DCR was 37.2% and 37.4%, respectively, in cohorts A and B. Based on the training set analysis, CPS 1 and 10 were selected for evaluation in the confirmation set. In the confirmation set, ORR was 4.1% for CPS <1, 5.7% CPS ≥1, and 10.0% for CPS ≥10. PFS was 2.1 months for both cohorts. Median OS was not reached for cohort A and was 17.6 months for cohort B. Toxicities were consistent with other single-agent pembrolizumab trials. CONCLUSIONS: Single-agent pembrolizumab showed modest activity in patients with ROC. Higher PD-L1 expression was correlated with higher response. CLINICAL TRIAL NUMBER: Clinicaltrials.gov, NCT02674061.
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Adenocarcinoma de Células Claras/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adenocarcinoma de Células Claras/patología , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Estudios de Cohortes , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/patología , Pronóstico , Tasa de SupervivenciaAsunto(s)
Neoplasias Endometriales , Inestabilidad de Microsatélites , Anticuerpos Monoclonales Humanizados , Reparación de la Incompatibilidad de ADN/genética , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Femenino , Humanos , Repeticiones de Microsatélite , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genéticaRESUMEN
PURPOSE OF INVESTIGATION: A retrospective study to evaluate six cycles of cisplatin 40 mg/m2 on day 1 and ifosfamide 1,200 mg/m2 daily on days 1 to 4 with Mesna every four weeks as first line treatment for 29 patients with a diagnosis of uterine carcinosarcoma. MATERIALS AND METHODS: A total of 23 of 29 patients received high dose rate intracavitary vaginal cuff brachytherapy (VCBT) with two fractions of seven Gy each. Median age was 65 years (range 40-82); 13 (44.8%) had Stage I disease, three (10.3%) had Stage II, eight (27.6%) had Stage III, and five (17.2%) patients had Stage IV disease. RESULTS: Most common toxicities were anemia grade 1 (35%)/grade 2 (45%), and neutropenia grade 3 (17%)/grade 4 (6.9%). Eleven dose modifications, four treatment discontinuations, and one patient withdrawal occurred. At a median follow up of 45 months (range 9 to 144), Progression free survival (PFS) was 20% and overall survival (OS) was 40% for Stage IV, PFS 75% and OS 62.5% for Stage III, compared to a PFS 75% and OS 72.2% for Stages I-II. Median OS for the entire group was 12.43 years (95% CI 3.69 to inf); for Stage I-III 12.4 years (6.1 to inf), and for Stage IV 15.6 months (95% CI 9.4 to inf). CONCLUSIONS: Cisplatin and ifosfamide chemotherapy with VCBT was well tolerated and has promising activity in uterine carcinosarcoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Braquiterapia/métodos , Carcinosarcoma/terapia , Neoplasias Uterinas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Carcinosarcoma/patología , Quimioradioterapia , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Ifosfamida/administración & dosificación , Mesna/uso terapéutico , Persona de Mediana Edad , Estadificación de Neoplasias , Neutropenia/inducido químicamente , Sustancias Protectoras/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias Uterinas/patologíaRESUMEN
BACKGROUND: Uterine serous carcinomas (USCs) are an aggressive form of uterine cancer that may rely on HER2/neu amplification as a driver of proliferation. The objective of this paper is to assess the sensitivity of USC cell lines with and without HER2/neu gene amplification to afatinib, an irreversible ErbB tyrosine kinase inhibitor, and to test the efficacy of afatinib in the treatment of HER2-amplified USC xenografts. METHODS: Eight of fifteen primary USC cell lines (four with HER2 amplification and four without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signalling and cell cycle distribution were determined by flow cytometry assays. Mice harbouring xenografts of HER2/neu-amplified USC were treated with afatinib by gavage to determine the effect on tumour growth and overall survival. RESULTS: Primary chemotherapy-resistant USC cell lines harbouring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean ± s.e.m. IC50=0.0056 ± 0.0006 µM) and significantly more sensitive than HER2/neu-non-amplified USC cell lines (mean ± s.e.m. IC50=0.563 ± 0.092 µM, P<0.0001). Afatinib exposure resulted in abrogation of cell survival, inhibition of HER2/neu autophosphorylation and S6 transcription factor phosphorylation in HER2/neu overexpressing USC and inhibited the growth of HER2-amplified tumour xenografts improving overall survival (P=0.0017). CONCLUSIONS: Afatinib may be highly effective against HER2/neu-amplified chemotherapy-resistant USC. The investigation of afatinib in patients harbouring HER2/neu-amplified USC is warranted.
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Cistadenocarcinoma Seroso/tratamiento farmacológico , Neoplasias Endometriales/tratamiento farmacológico , Quinazolinas/farmacología , Receptor ErbB-2/metabolismo , Neoplasias Uterinas/tratamiento farmacológico , Adulto , Afatinib , Anciano , Anciano de 80 o más Años , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patología , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Femenino , Humanos , Técnicas para Inmunoenzimas , Hibridación Fluorescente in Situ , Técnicas In Vitro , Ratones , Ratones SCID , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Receptor ErbB-2/genética , Transducción de Señal/efectos de los fármacos , Células Tumorales Cultivadas , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: We studied the genetic fingerprints of ovarian cancer and validated the potential of Mammaglobin b (SCGB2A1), one of the top differentially expressed genes found in our analysis, as a novel ovarian tumour rejection antigen. METHODS: We profiled 70 ovarian carcinomas including 24 serous (OSPC), 15 clear-cell (CC), 24 endometrioid (EAC) and 7 poorly differentiated tumours, and 14 normal human ovarian surface epithelial (HOSE) control cell lines using the Human HG-U133 Plus 2.0 chip (Affymetrix). Quantitative real-time PCR and immunohistochemistry staining techniques were used to validate microarray data at RNA and protein levels for SCGB2A1. Full-length human-recombinant SCGB2A1 was used to pulse monocyte-derived dendritic cells (DCs) to stimulate autologous SCGB2A1-specific cytotoxic T-lymphocyte (CTL) responses against chemo-naive and chemo-resistant autologous ovarian tumours. RESULTS: Gene expression profiling identified SCGB2A1 as a top differentially expressed gene in all histological ovarian cancer types tested. The CD8+ CTL populations generated against SCGB2A1 were able to consistently induce lysis of autologous primary (chemo-naive) and metastatic/recurrent (chemo-resistant) target tumour cells expressing SCGB2A1, whereas autologous HLA-identical noncancerous cells were not lysed. Cytotoxicity against autologous tumour cells was significantly inhibited by anti-HLA-class I (W6/32) monoclonal antibody. Intracellular cytokine expression measured by flow cytometry showed a striking type 1 cytokine profile (i.e., high IFN-γ secretion) in SCGB2A1-specific CTLs. CONCLUSION: SCGB2A1 is a top differentially expressed gene in all major histological types of ovarian cancers and may represent a novel and attractive target for the immunotherapy of patients harbouring recurrent disease resistant to chemotherapy.
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Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Mamoglobina B/metabolismo , Neoplasias Ováricas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Neoplasias/genética , Biomarcadores de Tumor/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoterapia , Mamoglobina B/genética , Análisis por Micromatrices , Persona de Mediana Edad , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Transcriptoma , Estudios de Validación como AsuntoRESUMEN
Glycation occurs when glucose reacts non-enzymatically with proteins. This reaction depends upon time, ambient glucose concentration, and the molecular conformation of reactive amino acids. Little is known about protein glycation in fishes and the main objective of this study was to measure glycated hemoglobin (GHb) in rainbow trout, a glucose-intolerant species, under normoglycemic and hyperglycemic conditions. We also identified GHb isoforms in vivo and analyzed the structural environment surrounding potential glycation sites. Despite similar glycemia to healthy humans, GHb was an order of magnitude lower in rainbow trout (0.6%) compared with humans (6%) and was not affected by long-term hyperglycemia. Species differences in GHb appear to be related to differences in erythrocyte glucose, and differential expression and glycation of hemoglobin (Hb) isoforms may explain intraspecific differences in rainbow trout GHb. Computer analysis of glucose isomers (ringed-open and α- and ß-pyranoses) interacting with the ß-chain of rainbow trout HbI and HbIV, and human HbA did not reveal structural or energetic constraints for glucose binding (the initial step of glycation) for rainbow trout Hbs. Overall, there are significant differences between Hb glycation in humans and rainbow trout, and GHb does not appear to be an accurate indicator of glycemia over time in rainbow trout.
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Glucemia/metabolismo , Glucosa/metabolismo , Hemoglobina Glucada/metabolismo , Animales , Eritrocitos/metabolismo , Femenino , Glicosilación , Humanos , Masculino , Oncorhynchus mykiss , Isoformas de ProteínasRESUMEN
Artisanal fisheries, although considered less harmful, can still endanger marine ecosystems, especially in areas with long-standing tradition. In Cap de Creus, where artisanal fisheries has likely occurred for centuries, the status of benthic communities in fishing grounds was poorly understood. Through collaboration with local fishers, the benthic assemblages in three artisanal fishing grounds within Cap de Creus Marine Protected Area (MPA) were studied. Using video transects recorded by a remotely operated vehicle (ROV), the diversity and distribution of species were analysed in relation to substrate type, slope, and depth. The study also assessed the impacts on these communities by examining marine litter, lost fishing gear, and the condition of gorgonian populations. The findings identified three megabenthic assemblages and revealed higher fishing pressure and impact in the Maça d'Oros area, likely due to multiple fishing guilds converging. However, the study demonstrated lower impact in MPAs compared to unprotected Mediterranean areas, highlighting the importance of coastal management.
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Ecosistema , Explotaciones Pesqueras , Mar Mediterráneo , Conservación de los Recursos NaturalesRESUMEN
BACKGROUND: Leg ulcers associated with major sickle cell disease (SCLU) are a chronic, painful complication, often treated by autologous skin graft. The analgesic effect of skin grafting in SCLU is poorly studied. The aim of this study was to evaluate the effect of skin grafting on the pain and healing of SCLU. METHODS: Patients hospitalized for SCLU skin grafting were included in a retrospective and prospective observational cohort, between 2019 and 2023: 53 autologous pinch grafts were performed on a total of 35 SCLUs in 25 sickle cell patients. The primary endpoint was the evaluation of the analgesic effect of the skin graft, measured by visual analog scale (VAS) and weekly cumulative analgesic consumption between day (D)0, D7 and D30. Wound healing was assessed by variation in wound areas between D0 and D30. RESULTS: Twenty-five patients with a median age range of 45.5years old were included, 68% were men, SS genotype was present in 96% of the cases. At D7, a significant decrease in VAS and consumption of analgesics of all classes was observed. At D30, only a significant decrease in VAS and consumption of mild opioids was present, as well as a significant reduction in wound surface area compared with D0. CONCLUSION: Pinch grafts have a significant early analgesic effect in the management of patients with SCLU, and significantly notice reduction of wound surface area within one month.
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Anemia de Células Falciformes , Úlcera de la Pierna , Femenino , Humanos , Masculino , Persona de Mediana Edad , Analgésicos/uso terapéutico , Anemia de Células Falciformes/complicaciones , Úlcera de la Pierna/tratamiento farmacológico , Úlcera de la Pierna/etiología , Úlcera de la Pierna/cirugía , Dolor , Estudios Retrospectivos , Trasplante de Piel/efectos adversos , Estudios ProspectivosRESUMEN
BACKGROUND: We evaluated the expression of CD46, CD55 and CD59 membrane-bound complement-regulatory proteins (mCRPs) in primary uterine serous carcinoma (USC) and the ability of small interfering RNA (siRNA) against these mCRPs to sensitise USC to complement-dependent cytotoxicity (CDC) and antibody (trastuzumab)-dependent cellular cytotoxicity (ADCC) in vitro. METHODS: Membrane-bound complement-regulatory proteins expression was evaluated using real-time PCR (RT-PCR) and flow cytometry, whereas Her2/neu expression and c-erbB2 gene amplification were assessed using immunohistochemistry, flow cytometry and fluorescent in-situ hybridisation. The biological effect of siRNA-mediated knockdown of mCRPs on HER2/neu-overexpressing USC cell lines was evaluated in CDC and ADCC 4-h chromium-release assays. RESULTS: High expression of mCRPs was found in USC cell lines when compared with normal endometrial cells (P<0.05). RT-PCR and FACS analyses demonstrated that anti-mCRP siRNAs were effective in reducing CD46, CD55 and CD59 expression on USC (P<0.05). Baseline complement-dependent cytotoxicity (CDC) against USC cell lines was low (mean ± s.e.m.=6.8 ± 0.9%) but significantly increased upon CD55 and CD59 knockdown (11.6 ± 0.8% and 10.7 ± 0.9%, respectively, P<0.05). Importantly, in the absence of complement, both CD55 and CD59, but not CD46, knockdowns significantly augmented ADCC against USC overexpressing Her2/neu. CONCLUSION: Uterine serous carcinoma express high levels of the mCRPs CD46, CD55 and CD59. Small interfering RNA inhibition of CD55 and CD59, but not CD46, sensitises USC to both CDC and ADCC in vitro, and if specifically targeted to tumour cells, may significantly increase trastuzumab-mediated therapeutic effect in vivo.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Citotoxicidad Celular Dependiente de Anticuerpos , Antígenos CD55/metabolismo , Antígenos CD59/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias del Cuello Uterino/metabolismo , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Antígenos CD55/química , Antígenos CD55/genética , Antígenos CD59/química , Antígenos CD59/genética , Activación de Complemento , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/inmunología , Citotoxicidad Inmunológica , Regulación hacia Abajo , Femenino , Citometría de Flujo , Humanos , Hibridación Fluorescente in Situ , Proteína Cofactora de Membrana/genética , Proteína Cofactora de Membrana/metabolismo , Persona de Mediana Edad , Pronóstico , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor ErbB-2/genética , Trastuzumab , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/inmunologíaRESUMEN
BACKGROUND: We evaluated shedding of epidermal growth factor type II receptor (Her2/neu) extracellular domain (ECD) in primary uterine serous carcinoma (USC) cell lines and in the serum of USC patients and its biological effects in experiments of trastuzumab-induced cytotoxicity in vitro. METHODS: Her2/neu expression was evaluated by immunohistochemistry (IHC), real-time PCR and flow cytometry, while c-erbB2 gene amplification was assessed using fluorescent in situ hybridisation (FISH). Her2/neu ECD levels in the supernatants of USC cell lines and in the serum of 38 USC patients and 19 controls were tested using ELISA. The biologic effect of Her2/neu ECD on trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated in 5-h chromium-release assays. RESULTS: Five out of ten USC cell lines overexpressed Her2/neu by IHC and showed amplification of the c-erbB2 gene. High levels of Her2/neu ECD were found in supernatants of all FISH-positive tumours. In contrast, FISH-negative USC was negative for Her2/neu ECD shedding. Serum Her2/neu ECD levels in patients harbouring 3+Her2/neu tumours were higher than those found in healthy women (P=0.02) or USC patients with 2+ or 1+/negative Her2/neu expression (P=0.02). In cytotoxicity experiments, trastuzumab-mediated ADCC was significantly decreased by the addition of Her2/neu ECD-containing supernatants (P=0.01). CONCLUSION: FISH-positive c-erbB2 USC cell lines shed high levels of Her2/neu ECD. High levels of Her2/neu ECD in USC patients may reduce trastuzumab-mediated ADCC in vitro and potentially neutralise its therapeutic effect in vivo.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Genes erbB-2 , Neoplasias Uterinas/metabolismo , Anciano , Anciano de 80 o más Años , Citotoxicidad Celular Dependiente de Anticuerpos , Medios de Cultivo Condicionados , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Inmunoterapia , Hibridación Fluorescente in Situ , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Trastuzumab , Neoplasias Uterinas/genética , Neoplasias Uterinas/patología , Neoplasias Uterinas/terapiaRESUMEN
In 2015, the Nobel Committee for Physiology or Medicine, in its only award for treatments of infectious diseases since six decades prior, honoured the discovery of ivermectin (IVM), a multifaceted drug deployed against some of the world's most devastating tropical diseases. Since March 2020, when IVM was first used against a new global scourge, COVID-19, more than 20 randomized clinical trials (RCTs) have tracked such inpatient and outpatient treatments. Six of seven meta-analyses of IVM treatment RCTs reporting in 2021 found notable reductions in COVID-19 fatalities, with a mean 31% relative risk of mortality vs. controls. During mass IVM treatments in Peru, excess deaths fell by a mean of 74% over 30 days in its ten states with the most extensive treatments. Reductions in deaths correlated with the extent of IVM distributions in all 25 states with p < 0.002. Sharp reductions in morbidity using IVM were also observed in two animal models, of SARS-CoV-2 and a related betacoronavirus. The indicated biological mechanism of IVM, competitive binding with SARS-CoV-2 spike protein, is likely non-epitope specific, possibly yielding full efficacy against emerging viral mutant strains.
RESUMEN
BACKGROUND: Uterine serous papillary adenocarcinoma (USPC) is a highly aggressive variant of endometrial cancer. Human immuno-conjugate molecule (hI-con1) is an antibody-like molecule targeted against tissue factor (TF), composed of two human Factor VII (fVII) as the targeting domain, fused to human immunoglobulin (Ig) G1 Fc as an effector domain. We evaluated hI-con1 potential activity against primary chemotherapy-resistant USPC cell lines expressing different levels of TF. METHODS: A total of 16 formalin-fixed, paraffin-embedded USPC samples were evaluated by immunohistochemistry (IHC) for TF expression. Six primary USPC cell lines, half of which overexpress the epidermal growth factor type II (HER2/neu) receptor at 3+ levels, were assessed by flow cytometry and real-time PCR for TF expression. Sensitivity to hI-con1-dependent cell-mediated cytotoxicity (IDCC) was evaluated in 5-hour-chromium release assays. Finally, to investigate the effect of interleukin-2 (IL-2) on IDCC, 5-h (51)Cr assays were also conducted in the presence of low doses of IL-2 (i.e., 50-100 IU ml(-1)). RESULTS: Cytoplasmic and/or membrane TF expression was observed in all 16 (100%) USPC samples tested by IHC, but not in normal endometrium. High expression of TF was found in 50% (three out of six) of the USPC cell lines tested by real-time PCR and flow cytometry when compared with normal endometrial cells (NECs; P<0.001). Uterine serous papillary adenocarcinoma cell lines overexpressing TF, regardless of their high or low HER2/neu expression, were highly sensitive to IDCC (mean killing+/-s.d., 65.6+/-3.7%, range 57.5-77.0%, P<0.001), although negligible cytotoxicity against USPC was seen in the absence of hI-con1 or in the presence of Rituximab control antibody. The addition of low doses of IL-2 further increased the cytotoxic effect induced by hI-con1 against chemotherapy-resistant USPC. CONCLUSION: hI-con1 induces strong cytotoxicity against primary chemotherapy-resistant USPC cell lines overexpressing TF. The hI-con1 may represent a novel therapeutic agent for the treatment of patients harbouring advanced, recurrent and/or metastatic USPC refractory to standard treatment modalities.
Asunto(s)
Carcinoma Papilar/terapia , Factor VII/uso terapéutico , Inmunoterapia , Proteínas Recombinantes de Fusión/uso terapéutico , Neoplasias Uterinas/terapia , Carcinoma Papilar/inmunología , Carcinoma Papilar/patología , Línea Celular Tumoral , Femenino , Humanos , Inmunohistoquímica , Células Asesinas Naturales/inmunología , Reacción en Cadena de la Polimerasa , Neoplasias Uterinas/inmunología , Neoplasias Uterinas/patologíaRESUMEN
BACKGROUND: Uterine serous papillary adenocarcinoma (USPC) is a rare but highly aggressive variant of endometrial cancer. Pertuzumab is a new humanised monoclonal antibody (mAb) targeting the epidermal growth factor type II receptor (HER2/neu). We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu. METHODS: Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time PCR for HER2/neu expression. c-erbB2 gene amplification was evaluated using fluorescent in situ hybridisation (FISH). Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays. Pertuzumab cytostatic activity was evaluated using proliferation-based assays. RESULTS: Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH. The remaining FISH-negative USPCs expressed HER2/neu at 0/1+ levels. In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC. The addition of complement-containing plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs. In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC. Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (P=0.02). Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression. CONCLUSION: Pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines. Pertuzumab significantly increases tratuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic agent in patients harbouring advanced/recurrent and/or refractory USPC.
Asunto(s)
Adenocarcinoma Papilar/patología , Anticuerpos Monoclonales/farmacología , Neoplasias Uterinas/patología , Anciano , Anticuerpos Monoclonales Humanizados , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Proteínas del Sistema Complemento/inmunología , Citotoxicidad Inmunológica , Dimerización , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Humanos , Inmunoglobulina G/inmunología , Técnicas In Vitro , Interleucina-2/farmacología , Células Asesinas Naturales/inmunología , Linfocitos/inmunología , Persona de Mediana Edad , Receptor ErbB-2/biosíntesis , Receptor ErbB-2/genética , Receptor ErbB-2/inmunología , Transducción de Señal/efectos de los fármacos , TrastuzumabRESUMEN
An essential oil was recently extracted from the leaves and flowers of yarrow (Achillea millefolium) and tested for in-vitro activity against Leishmania amazonensis and murine macrophages (i.e. the J774G8 cell line). The median inhibitory concentration (IC(50)) against L. amazonensis promastigotes was 7.8 µg/ml whereas the survival of amastigotes of this pathogen, within peritoneal murine macrophages, was halved by treatment with the oil at 6.5 µg/ml. The mean value for the median cytotoxic concentration of the oil, measured against adherent (uninfected) J774G8 macrophages, was 72.0 µg/ml (i.e. 9.2 and 11.0 times higher, respectively, than the IC(50) against the promastigotes and intracellular amastigotes). Scanning electron microscopy revealed that the oil caused morphological changes in the treated parasites, including alterations in their shape and size. In transmission electron microscopy, promastigotes treated with the oil (at the IC(50) of 7.8 µg/ml) showed various ultrastructural alterations, including changes in the flagellar membrane, abnormal membrane structures, rupture of the plasma membrane, atypical vacuoles, myelin-like figures, and vesicles that resembled autophagic vacuoles.
Asunto(s)
Achillea , Antiprotozoarios/farmacología , Leishmania/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Aceites Volátiles/farmacología , Aceites de Plantas/farmacología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Flores/química , Concentración 50 Inhibidora , Leishmania/ultraestructura , Macrófagos Peritoneales/parasitología , Ratones , Microscopía Electrónica de Rastreo , Aceites Volátiles/química , Pruebas de Sensibilidad Parasitaria , Hojas de la Planta/químicaRESUMEN
Nowadays, there are an increasing number of reports of deep-sea accumulation of marine debris, often associated with a wide array of pernicious effects on benthic fauna. Nevertheless, there is still a huge knowledge gap regarding the interaction of benthic organisms and marine debris. In this paper, we report for the first time the colonization of plastic debris by the protected sponges Lycopodina hypogea. The sponges were discovered growing on plastic debris tangled with nylon ropes on the Blanes canyon (northwestern Mediterranean Sea). Over 30 individuals of L. hypogea were identified attached on ca. 10â¯cm2 plastic debris, an unusual feature for a species mostly known for low-density populations and a patchy distribution. The implications of this discovery are discussed, and it is suggested that marine debris might provide substrate for benthic species on otherwise unsuitable habitats, with its possible role as stepping-stones for deep-sea benthic connectivity needing further study.
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Monitoreo del Ambiente , Plásticos , Carnivoría , Ecosistema , Mar Mediterráneo , Residuos/análisisRESUMEN
BACKGROUND: Uterine serous papillary carcinoma (USPC) is a biologically aggressive variant of endometrial cancer. We investigated the expression of Serum Amyloid A (SAA) and evaluated its potential as a serum biomarker in USPC patients. METHODS: SAA gene and protein expression levels were evaluated in USPC and normal endometrial tissues (NEC) by real-time PCR, immunohistochemistry (IHC), flow cytometry and by a sensitive bead-based immunoassay. SAA concentration in 123 serum samples from 51 healthy women, 42 women with benign diseases, and 30 USPC patients were also studied. RESULTS: SAA gene expression levels were significantly higher in USPC when compared with NEC (mean copy number by RT-PCR=162 vs 2.21; P=0.0002). IHC revealed diffuse cytoplasmic SAA protein staining in USPC tissues. High intracellular levels of SAA were identified in primary USPC cell lines evaluated by flow cytometry and SAA was found to be actively secreted in vitro. SAA concentrations (mug ml(-1)) had a median (95% CIs) of 6.0 (4.0-8.9) in normal healthy females and 6.0 (4.2-8.1) in patients with benign disease (P=0.92). In contrast, SAA values in the serum of USPC patients had a median (95% CI) of 15.6 (9.2-56.2), significantly higher than those in the healthy group (P=0.0005) and benign group (P=0.0006). Receiver operating characteristics (ROC) analysis of serum SAA to classify advanced- and early-stage USPC yielded an area under the ROC curve of 0.837 (P=0.0024). CONCLUSION: SAA is not only a liver-secreted protein but is also a USPC cell product. SAA may represent a novel biomarker for USPC to assist in staging patients preoperatively, and to monitor early-disease recurrence and response to therapy.
Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma Papilar/sangre , Cistadenocarcinoma Seroso/sangre , Proteína Amiloide A Sérica/biosíntesis , Neoplasias Uterinas/sangre , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Carcinoma Papilar/genética , Carcinoma Papilar/patología , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patología , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Estadificación de Neoplasias , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína Amiloide A Sérica/genética , Células Tumorales Cultivadas , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologíaRESUMEN
The care in the emergencies of the renal colic at the adult was the object in 1999 of a conference of consensus of the French Society of Emergency (SFMU) in association with the French Association of Urology and the Society of Nephrology. This already former text was the object of an update in 2008 by the subcommittee of scientific monitoring of the SFMU and was presented to the congress 2008. This public presentation in the presence of an expert urologist allowed to confront this new text with the practices and to publish an updating of the conference of consensus of 1999. A survey of practice was led with the emergency physicians, whose results are presented.