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BACKGROUND AND PURPOSE: Early detection of residual or recurrent disease is important for effective salvage treatment in patients with head and neck cancer. Current National Comprehensive Cancer Network guidelines do not recommend standard surveillance imaging beyond 6 months unless there are worrisome signs or symptoms on clinical examination and offer vague guidelines for imaging of high-risk patients beyond that timeframe. Our goal was to evaluate the frequency of clinically occult recurrence in patients with head and neck squamous cell carcinoma with positive imaging findings (Neck Imaging Reporting and Data Systems scores of 2-4), especially after 6 months. MATERIALS AND METHODS: This institutional review board-approved, retrospective data base search queried neck CT reports with Neck Imaging Reporting and Data Systems scores of 2-4 from June 2014 to March 2018. The electronic medical records were reviewed to determine outcomes of clinical and radiologic follow-up, including symptoms, physical examination findings, pathologic correlation, and clinical notes within 3 months of imaging. RESULTS: A total of 255 cases, all with Neck Imaging Reporting and Data Systems scores of 2 or 3, met the inclusion criteria. Fifty-nine patients (23%) demonstrated recurrence (45 biopsy-proven, 14 based on clinical and imaging progression), and 21 patients (36%) had clinically occult recurrence (ie, no clinical evidence of disease at the time of the imaging examination). The median overall time to radiologically detected, clinically occult recurrence was 11.4 months from treatment completion. CONCLUSIONS: Imaging surveillance beyond the first posttreatment baseline study was critical for detecting clinically occult recurrent disease in patients with head and neck squamous cell carcinoma. More than one-third of all recurrences were seen in patients without clinical evidence of disease; and 81% of clinically occult recurrences occurred beyond 6 months.
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Detección Precoz del Cáncer/métodos , Recurrencia Local de Neoplasia/diagnóstico por imagen , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico por imagen , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos , Resultado del TratamientoRESUMEN
Use of growth factor after high-dose chemotherapy (HDC) and autologous peripheral blood stem cell (PBSC) support is current standard in reducing days of neutropenia. This retrospective study aims to compare the efficacy of two standard growth factors, pegfilgrastim (PEG) and filgrastim (FIL) after HDC. We collected data on 195 consecutive adult patients who received an autotransplant (myeloma, lymphoma and others) between January 2004 and December 2014 at two tertiary care centres. The primary end point was the duration of neutropenia in terms of days to reach an ANC > 0.5 × 109/L. Filgrastim was given to 110 patients and PEG was given to 85 patients. Time to engraftment, defined as the time to reach an ANC of 0.5 × 109/L on 2 consecutive days after the day of auto-SCT, was 12.6 days with FIL compared with 12.1 days with PEG group (p = 0.126). When comparing the total days of severe neutropenia (WBC < 0.1 × 109/L), there were 5.5 days of severe neutropenia with FIL compared with 5.8 days with PEG group (p = 0.7). The duration of febrile neutropenia was an average of 5.3 days with FIL and 4.6 days with PEG (p = 0.029). The total number of antibiotic days was shorter for the patients who received PEG, being 11.08 days with PEG and 12.1 days with FIL (p = 0.184).The average cost savings per person in terms of number of days of hospitalization and number of days of total parental nutrition was 582 Rs (p = 0.512) and 6003 Rs (p = 0.018) respectively in favour of PEG arm. PEG is similar to FIL in hematological reconstitution, however it is more cost effective alternative after HDC and PBSC.
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Engraftment Syndrome (ES) maybe observed in patients who undergo autologous stem cell transplant (SCT). To investigate clinical criteria for ES diagnosis and analyse the risk factors for this complication, we reviewed all auto-SCT cases (Lymphoma and Myeloma) performed during the past 9 years at two tertiary care centres. We analysed all patients with a non-infectious fever, developed within 7 days of engraftment (first day of ANC of 500 on two consecutive days) in 178 patients undergoing autologous stem cell transplant. A total of 46/178 (25.8%) patients developed non-infectious fever and one or more clinical signs of ES within 7 days of engraftment. In all, 29 (61%) fulfilled the Maiolino and 12 (26%) the Spitzer criteria. The incidence of engraftment syndrome using the Maiolino criteria in our study was 29 (15%), which compares well with Spanish study (13% using same criteria) and the original Maiolino study (20%). All patients with ES satisfactorily recovered and discharged with a median of 20 days from hospital. There was no significant difference in number of days of hospitalisation and days of antibiotics between the ES and non ES arms. All patients recovered without any morbidity and only 1 (2%) patient required readmission for fungal pneumonitis. 8 (17%) patients required ICU admission due to delay in initiation of steroids. None of the factors including number of chemotherapy cycles, conditioning regime, disease status, CD34 collection, growth factors and day of WBC engraftment except female (p = 0.064) were statistically significant (in univariate or multivariate analysis). Our study shows that engraftment syndrome is common in autologous transplant setting. Maiolino criteria to diagnose ES is more sensitive in our setting. If detected and treated early there is not much morbidity or mortality related to ES.
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Nonsmall cell lung cancer (NSCLC) is increasingly being treated with targeted therapies. Epidermal growth factor receptor (EGFR) has been extensively studied in NSCLC as an oncogenic driver. However, the efficacy of the EGFR tyrosine kinase inhibitors (TKIs) is adversely impacted by the development of resistance. The occurrence of de novo resistance to EGFR TKIs is attributed to multiple mechanisms such as point mutations of oncogenes and chromosomal rearrangements. The development of acquired resistance to EGFR TKIs is facilitated by secondary mutations, phenotypical transformation, aberrance of downstream pathways, and activation of alternate signaling pathways. The T790M mutation is the most common mutation that accounts for about half of the acquired resistance to EGFR TKIs. This review article provides an overview of the common oncogenic drivers, targeted therapies for NSCLC, and the established mechanisms implicated in the development of resistance to the EGFR TKIs.
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Carcinogénesis/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos/genética , Humanos , Terapia Molecular Dirigida , Mutación , Proteínas Tirosina Quinasas/antagonistas & inhibidoresRESUMEN
Blood vessels supply tissues and organs with oxygen, nutrients, cellular, and humoral factors, while lymphatic vessels regulate tissue fluid homeostasis, immune trafficking, and dietary fat absorption. Understanding the mechanisms of vascular morphogenesis has become a subject of intense clinical interest because of the close association of both types of vessels with pathogenesis of a broad spectrum of human diseases. The zebrafish provides a powerful animal model to study vascular morphogenesis because of their small, accessible, and transparent embryos. These unique features of zebrafish embryos permit sophisticated high-resolution live imaging of even deeply localized vessels during embryonic development and even in adult tissues. In this chapter, we summarize various methods for blood and lymphatic vessel imaging in zebrafish, including nonvital resin injection-based or dye injection-based vessel visualization, and alkaline phosphatase staining. We also provide protocols for vital imaging of vessels using microangiography or transgenic fluorescent reporter zebrafish lines.
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Vasos Sanguíneos/citología , Embrión no Mamífero/citología , Larva/citología , Vasos Linfáticos/citología , Pez Cebra/crecimiento & desarrollo , Animales , Fluorescencia , Expresión Génica , Modelos Animales , Imagen ÓpticaRESUMEN
The Endocrine Society's first Scientific Statement in 2009 provided a wake-up call to the scientific community about how environmental endocrine-disrupting chemicals (EDCs) affect health and disease. Five years later, a substantially larger body of literature has solidified our understanding of plausible mechanisms underlying EDC actions and how exposures in animals and humans-especially during development-may lay the foundations for disease later in life. At this point in history, we have much stronger knowledge about how EDCs alter gene-environment interactions via physiological, cellular, molecular, and epigenetic changes, thereby producing effects in exposed individuals as well as their descendants. Causal links between exposure and manifestation of disease are substantiated by experimental animal models and are consistent with correlative epidemiological data in humans. There are several caveats because differences in how experimental animal work is conducted can lead to difficulties in drawing broad conclusions, and we must continue to be cautious about inferring causality in humans. In this second Scientific Statement, we reviewed the literature on a subset of topics for which the translational evidence is strongest: 1) obesity and diabetes; 2) female reproduction; 3) male reproduction; 4) hormone-sensitive cancers in females; 5) prostate; 6) thyroid; and 7) neurodevelopment and neuroendocrine systems. Our inclusion criteria for studies were those conducted predominantly in the past 5 years deemed to be of high quality based on appropriate negative and positive control groups or populations, adequate sample size and experimental design, and mammalian animal studies with exposure levels in a range that was relevant to humans. We also focused on studies using the developmental origins of health and disease model. No report was excluded based on a positive or negative effect of the EDC exposure. The bulk of the results across the board strengthen the evidence for endocrine health-related actions of EDCs. Based on this much more complete understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability, these findings can be much better translated to human health. Armed with this information, researchers, physicians, and other healthcare providers can guide regulators and policymakers as they make responsible decisions.
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Disruptores Endocrinos/toxicidad , Animales , Compuestos de Bencidrilo , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus/inducido químicamente , Diabetes Mellitus/epidemiología , Endocrinología , Exposición a Riesgos Ambientales , Femenino , Herbicidas , Humanos , Masculino , Neoplasias Hormono-Dependientes/epidemiología , Trastornos del Neurodesarrollo/inducido químicamente , Trastornos del Neurodesarrollo/epidemiología , Sistemas Neurosecretores/efectos de los fármacos , Obesidad/inducido químicamente , Obesidad/epidemiología , Plaguicidas , Fenoles , Ácidos Ftálicos/toxicidad , Neoplasias de la Próstata/inducido químicamente , Neoplasias de la Próstata/epidemiología , Reproducción/efectos de los fármacos , Sociedades Médicas , Glándula Tiroides/efectos de los fármacosRESUMEN
This Executive Summary to the Endocrine Society's second Scientific Statement on environmental endocrine-disrupting chemicals (EDCs) provides a synthesis of the key points of the complete statement. The full Scientific Statement represents a comprehensive review of the literature on seven topics for which there is strong mechanistic, experimental, animal, and epidemiological evidence for endocrine disruption, namely: obesity and diabetes, female reproduction, male reproduction, hormone-sensitive cancers in females, prostate cancer, thyroid, and neurodevelopment and neuroendocrine systems. EDCs such as bisphenol A, phthalates, pesticides, persistent organic pollutants such as polychlorinated biphenyls, polybrominated diethyl ethers, and dioxins were emphasized because these chemicals had the greatest depth and breadth of available information. The Statement also included thorough coverage of studies of developmental exposures to EDCs, especially in the fetus and infant, because these are critical life stages during which perturbations of hormones can increase the probability of a disease or dysfunction later in life. A conclusion of the Statement is that publications over the past 5 years have led to a much fuller understanding of the endocrine principles by which EDCs act, including nonmonotonic dose-responses, low-dose effects, and developmental vulnerability. These findings will prove useful to researchers, physicians, and other healthcare providers in translating the science of endocrine disruption to improved public health.
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Disruptores Endocrinos/toxicidad , Animales , Compuestos de Bencidrilo/toxicidad , Diabetes Mellitus/inducido químicamente , Diabetes Mellitus/epidemiología , Endocrinología , Exposición a Riesgos Ambientales , Epigénesis Genética , Femenino , Interacción Gen-Ambiente , Herbicidas/toxicidad , Humanos , Masculino , Neoplasias Hormono-Dependientes/inducido químicamente , Neoplasias Hormono-Dependientes/epidemiología , Trastornos del Neurodesarrollo/inducido químicamente , Trastornos del Neurodesarrollo/epidemiología , Sistemas Neurosecretores/efectos de los fármacos , Obesidad/inducido químicamente , Obesidad/epidemiología , Plaguicidas/toxicidad , Fenoles/toxicidad , Ácidos Ftálicos/toxicidad , Bifenilos Policlorados/toxicidad , Neoplasias de la Próstata/inducido químicamente , Neoplasias de la Próstata/epidemiología , Reproducción/efectos de los fármacos , Sociedades Médicas , Glándula Tiroides/efectos de los fármacosRESUMEN
Eye exposure to the extremely toxic organophosphorus sarin results in long-term miosis and visual impairment. As current treatment using atropine or homatropine eye drops may lead to considerable visual side effects, alternative combined treatments of intramuscular (im) oximes (16.8 µmol/kg, im) with atropine (0.5 mg/kg, im) or with the short acting antimuscarinic tropicamide (0.5%; w/v) eye drops were thus evaluated. The combined treatments efficacy following topical exposure to sarin (1 µg) was assessed by measuring pupil width and light reflex using an infra-red based digital photographic system. Results showed that the combined treatment of various oximes with atropine or with topical tropicamide eye drops rapidly reversed the sarin-induced miosis and presented a long-term improvement of 67-98% (oxime+tropicamide) or 84-109% (oxime+atropine) in pupil widening as early as 10-min following treatment. This recovery was shown to persist for at least 8-h following exposure. All combined treatments facilitated the ability of the iris to contract following sarin insult as tested by a light reflex response.Our findings emphasize the high efficacy of im oxime treatment combined with either atropine im or tropicamide eye drops in counteracting sarin-induced ocular insult. Therefore, in a mass casualty scenario the systemic combined treatment may be sufficient to ameliorate sarin-induced ocular insult with no need for additional, topical anticholinergic treatment at least in the initial stage of intoxication. For very mild casualties, who are unlikely to receive im treatment, the combined oxime (im) with topical tropicamide treatment may be sufficient in ameliorating the ocular insult.
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Atropina/farmacología , Reactivadores de la Colinesterasa/farmacología , Ojo/efectos de los fármacos , Oximas/farmacología , Sarín/toxicidad , Administración Oftálmica , Animales , Atropina/uso terapéutico , Sinergismo Farmacológico , Masculino , Miosis/tratamiento farmacológico , Ratas , Ratas Long-Evans , Tropicamida/administración & dosificación , Tropicamida/farmacologíaRESUMEN
OBJECTIVES: Accurate peripheral markers for the diagnosis of pancreatic ductal adenocarcinoma (PDAC) are lacking. We measured the differential expression of select microRNAs (miRNAs) in plasma and bile among patients with PDAC, chronic pancreatitis (CP), and controls. METHODS: We identified patients (n=215) with treatment-naive PDAC (n=77), CP with bile/pancreatic duct pathology (n=67), and controls (n=71) who had been prospectively enrolled in a Pancreatobiliary Biorepository at the time of endoscopic retrograde cholangiopancreatography or endoscopic ultrasound. Controls were patients with choledocholithiasis but normal pancreata. The sample was separated into training (n=95) and validation (n=120) cohorts to establish and then test the performance of PDAC Signature Panels in diagnosing PDAC. The training cohort (n=95) included age-matched patients with PDAC, CP, and controls. Panels were derived from the differential expression of 10 candidate miRNAs in plasma or bile. We selected miRNAs having excellent accuracy for inclusion in regression models. RESULTS: Using the training cohort, we confirmed the differential expression of 9/10 miRNAs in plasma (miR-10b, -30c, -106b, -132, -155, -181a, -181b, -196a, and -212) and 7/10 in bile (excluding miR-21, -132, and -181b). Of these, five (miR-10b, -155, -106b, -30c, and -212) had excellent accuracy for distinguishing PDAC. In the training and validation cohorts, the sensitivity/specificity for a PDAC Panel derived from plasma was 95/100% and 100/100%, respectively; in bile, these were 96/100% and 100/100%. CONCLUSIONS: Increased expression of miRNA-10b, -155, and -106b in plasma appears highly accurate in diagnosing PDAC. Additional studies are needed to confirm this Panel and explore its value as a prognostic test.
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Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias Pancreáticas/genética , Anciano , Bilis/química , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/metabolismo , Estudios de Casos y Controles , Femenino , Humanos , Masculino , MicroARNs/sangre , MicroARNs/metabolismo , Persona de Mediana Edad , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Proyectos Piloto , Sensibilidad y EspecificidadRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a poor prognosis that is characterized by excessive mitogenic pathway activation and marked chemoresistance to a broad spectrum of chemotherapeutic drugs. Dual specificity protein phosphatase 1 (DUSP1) is a key negative regulator of mitogen activated protein kinases (MAPKs). Yet, DUSP1 is overexpressed in pancreatic cancer cells (PCCs) in PDAC where it paradoxically enhances colony formation in soft agar and promotes in vivo tumorigenicity. However, it is not known whether DUSP1 overexpression contributes to PDAC chemoresistance. Using BxPC3 and COLO-357 human PCCs, we show that gemcitabine activates c-JUN N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38 MAPK), key kinases in two major stress-activated signaling pathways. Gemcitabine-induced JNK and p38 MAPK activation mediates increased apoptosis, but also transcriptionally upregulates DUSP1, as evidenced by increased DUSP1 mRNA levels and RNA polymerase II loading at DUSP1 gene body. Conversely, shRNA-mediated inhibition of DUSP1 enhances JNK and p38 MAPK activation and gemcitabine chemosensitivity. Using doxycycline-inducible knockdown of DUSP1 in established orthotopic pancreatic tumors, we found that combining gemcitabine with DUSP1 inhibition improves animal survival, attenuates angiogenesis, and enhances apoptotic cell death, as compared with gemcitabine alone. Taken together, these results suggest that gemcitabine-mediated upregulation of DUSP1 contributes to a negative feedback loop that attenuates its beneficial actions on stress pathways and apoptosis, raising the possibility that targeting DUSP1 in PDAC may have the advantage of enhancing gemcitabine chemosensitivity while suppressing angiogenesis.
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Antimetabolitos Antineoplásicos/farmacología , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/genética , Fosfatasa 1 de Especificidad Dual/genética , Neoplasias Pancreáticas/genética , Animales , Antimetabolitos Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Modelos Animales de Enfermedad , Fosfatasa 1 de Especificidad Dual/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Masculino , Ratones , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Transducción de Señal/efectos de los fármacos , Transcripción Genética , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , GemcitabinaRESUMEN
BACKGROUND AND PURPOSE: Eye exposure to the organophosphorus (OP) irreversible cholinesterase inhibitor sarin results in long-term miosis and impaired visual function. We have previously shown that tropicamide is better at ameliorating this insult than topical atropine or cyclopentolate. However, to minimize side effects associated with repeated tropicamide applications and high treatment doses, we evaluated the effects of oximes (ChE re-activators) alone and combined with tropicamide at ameliorating OP-induced ocular impairments. EXPERIMENTAL APPROACH: Rats were topically exposed to sarin, followed by topical treatment with various oximes alone or in combination with tropicamide. Pupil width and light reflex were measured by an infrared-based digital photograph system, while visual performance was assessed by employing the cueing version of the Morris water maze (MWM). KEY RESULTS: Oxime treatment following sarin ocular exposure induced a slow persistent pupil widening with efficacy in the order of HLö-7 > HI-6 > obidoxime = TMB-4 = MMB-4. In the light reflex test, the ability of the iris to contract following oxime treatment was mostly impaired at 1 h and was back to normal at 4 h following sarin exposure. All oxime treatments ameliorated the sarin-induced visual impairment as tested in the visual task (MWM). The combined topical treatment of tropicamide with an oxime induced a rapid improvement in pupil widening, light reflex and visual performance, and enabled a reduction in tropicamide dose. CONCLUSIONS AND IMPLICATIONS: The use of tropicamide combined with an oxime should be considered as the topical treatment of choice against the toxic effects of ocular OP exposure.
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Antagonistas Colinérgicos/administración & dosificación , Miosis/tratamiento farmacológico , Oximas/administración & dosificación , Sarín/toxicidad , Tropicamida/administración & dosificación , Trastornos de la Visión/tratamiento farmacológico , Administración Tópica , Animales , Quimioterapia Combinada , Masculino , Miosis/inducido químicamente , Ratas , Ratas Long-Evans , Resultado del Tratamiento , Trastornos de la Visión/inducido químicamenteRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is often associated with overexpression of TGF-ß. Given its tumor suppressor functions, it is unclear whether TGF-ß is a valid therapeutic target for PDAC. Here, we found that proliferating pancreatic cancer cells (PCCs) from human PDAC patients and multiple murine models of PDAC (mPDAC) often exhibit abundant levels of phosphorylated retinoblastoma 1 (RB) and Smad2. TGF-ß1 treatment enhanced proliferation of PCCs isolated from KrasG12D-driven mPDAC that lacked RB (KRC cells). This mitogenic effect was abrogated by pharmacological inhibition of type I TGF-ß receptor kinase, combined inhibition of MEK/Src or MEK/PI3K, and restoration of RB expression. TGF-ß1 promoted epithelial-to-mesenchymal transition (EMT), invasion, Smad2/3 phosphorylation, Src activation, Wnt reporter activity, and Smad-dependent upregulation of Wnt7b in KRC cells. Importantly, TGF-ß1-induced mitogenesis was markedly attenuated by inhibition of Wnt secretion. In an in vivo syngeneic orthotopic model, inhibition of TGF-ß signaling suppressed KRC cell proliferation, tumor growth, stroma formation, EMT, metastasis, ascites formation, and Wnt7b expression, and markedly prolonged survival. Together, these data indicate that RB dysfunction converts TGF-ß to a mitogen that activates known oncogenic signaling pathways and upregulates Wnt7b, which synergize to promote PCC invasion, survival, and mitogenesis. Furthermore, this study suggests that concomitantly targeting TGF-ß and Wnt7b signaling in PDAC may disrupt these aberrant pathways, which warrants further evaluation in preclinical models.