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The drug praziquantel (PZQ) is the key clinical therapy for treating schistosomiasis and other infections caused by parasitic flatworms. A schistosome target for PZQ was recently identified- a transient receptor potential ion channel in the melastatin subfamily (TRPMPZQ)-however, little is known about the properties of TRPMPZQ in other parasitic flatworms. Here, TRPMPZQ orthologs were scrutinized from all currently available parasitic flatworm genomes. TRPMPZQ is present in all parasitic flatworms, and the consensus PZQ binding site was well conserved. Functional profiling of trematode, cestode, and a free-living flatworm TRPMPZQ ortholog revealed differing sensitives (~300-fold) of these TRPMPZQ channels toward PZQ, which matched the varied sensitivities of these different flatworms to PZQ. Three loci of variation were defined across the parasitic flatworm TRPMPZQ pocketome with the identity of an acidic residue in the TRP domain acting as a gatekeeper residue impacting PZQ residency within the TRPMPZQ ligand binding pocket. In trematodes and cyclophyllidean cestodes, which display high sensitivity to PZQ, this TRP domain residue is an aspartic acid which is permissive for potent activation by PZQ. However, the presence of a glutamic acid residue found in other parasitic and free-living flatworm TRPMPZQ was associated with lower sensitivity to PZQ. The definition of these different binding pocket architectures explains why PZQ shows high therapeutic effectiveness against specific fluke and tapeworm infections and will help the development of better tailored therapies toward other parasitic infections of humans, livestock, and fish.
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Cestodos , Platelmintos , Canales Catiónicos TRPM , Trematodos , Animales , Praziquantel/farmacología , Schistosoma , Canales Catiónicos TRPM/metabolismoRESUMEN
Parasitic flatworms cause various clinical and veterinary infections that impart a huge burden worldwide. The most clinically impactful infection is schistosomiasis, a neglected tropical disease caused by parasitic blood flukes. Schistosomiasis is treated with praziquantel (PZQ), an old drug introduced over 40 years ago. New drugs are urgently needed, as while PZQ is broadly effective it suffers from several limitations including poor efficacy against juvenile worms, which may prevent it from being completely curative. An old compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). However, host side effects caused by benzodiazepines preclude development of MCLZ as a drug and MCLZ lacks an identified parasite target to catalyze rational drug design for engineering out human host activity. Here, we identify a transient receptor potential ion channel of the melastatin subfamily, named TRPMMCLZ, as a parasite target of MCLZ. MCLZ potently activates Schistosoma mansoni TRPMMCLZ through engagement of a binding pocket within the voltage-sensor-like domain of the ion channel to cause worm paralysis, tissue depolarization, and surface damage. TRPMMCLZ reproduces all known features of MCLZ action on schistosomes, including a lower activity versus Schistosoma japonicum, which is explained by a polymorphism within this voltage-sensor-like domain-binding pocket. TRPMMCLZ is distinct from the TRP channel targeted by PZQ (TRPMPZQ), with both anthelmintic chemotypes targeting unique parasite TRPM paralogs. This advances TRPMMCLZ as a novel druggable target that could circumvent any target-based resistance emerging in response to current mass drug administration campaigns centered on PZQ.
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Antihelmínticos , Clonazepam , Esquistosomiasis mansoni , Canales Catiónicos TRPM , Animales , Humanos , Antihelmínticos/farmacología , Benzodiazepinas/farmacología , Benzodiazepinonas/farmacología , Clonazepam/análogos & derivados , Clonazepam/farmacología , Praziquantel/farmacología , Schistosoma mansoni/efectos de los fármacos , Schistosoma mansoni/metabolismo , Esquistosomiasis mansoni/tratamiento farmacológico , Canales Catiónicos TRPM/agonistasRESUMEN
Substance P (SP) is released from sensory nerves in the arteries and heart. It activates neurokinin-1 receptors (NK1Rs) causing vasodilation, immune modulation, and adverse cardiac remodeling. The hypothesis was tested: SP and SP metabolites activate different second messenger signaling pathways. Macrophages, endothelial cells, and fibroblasts metabolized SP to N- and C-terminal metabolites to varying extents. SP 5-11 was the most abundant metabolite followed by SP 1-4, SP 7-11, SP 6-11, SP 3-11, and SP 8-11. In NK1R-expressing human embryonic kidney 293 (HEK293) cells, SP and some C-terminal SP metabolites stimulate the NK1R, promoting the dissociation of several Gα proteins, including Gαs and Gαq from their ßγ subunits. SP increases intracellular calcium concentrations ([Ca]i) and cyclic 3',5'-adenosine monophosphate (cAMP) accumulation with similar -log EC50 values of 8.5 ± 0.3 and 7.8 ± 0.1 M, respectively. N-terminal metabolism of SP by up to five amino acids and C-terminal deamidation of SP produce peptides that retain activity to increase [Ca]i but not to increase cAMP. C-terminal metabolism results in the loss of both activities. Thus, [Ca]i and cAMP signaling are differentially affected by SP metabolism. To assess the role of N-terminal metabolism, SP and SP 6-11 were compared with cAMP-mediated activities in NK1R-expressing 3T3 fibroblasts. SP inhibits nuclear factor κB (NF-κB) activity, cell proliferation, and wound healing and stimulates collagen production. SP 6-11 had little or no activity. Cyclooxygenase-2 (COX-2) expression is increased by SP but not by SP 6-11. Thus, metabolism may select the cellular response to SP by inhibiting or redirecting the second messenger signaling pathway activated by the NK1R.NEW & NOTEWORTHY Endothelial cells, macrophages, and fibroblasts metabolize substance P (SP) to N- and C-terminal metabolites with SP 5-11 as the most abundant metabolite. SP activates neurokinin-1 receptors to increase intracellular calcium and cyclic AMP. In contrast, SP metabolites of N-terminal metabolism and C-terminal deamidation retain the ability to increase calcium but lose the ability to increase cyclic AMP. These new insights indicate that the metabolism of SP directs cellular functions by regulating specific signaling pathways.
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AMP Cíclico , Receptores de Neuroquinina-1 , Transducción de Señal , Sustancia P , Sustancia P/metabolismo , Receptores de Neuroquinina-1/metabolismo , Receptores de Neuroquinina-1/agonistas , Humanos , AMP Cíclico/metabolismo , Animales , Células HEK293 , Ratones , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Calcio/metabolismoRESUMEN
Flexible optoelectronics is the need of the hour as the market moves toward wearable and conformable devices. Crystalline π-conjugated materials offer high performance as active materials compared to their amorphous counterpart, but they are typically brittle. This poses a significant challenge that needs to be overcome to unfold their potential in optoelectronic devices. Unveiling the molecular packing topology and identifying interaction descriptors that can accommodate strain offers essential guiding principles for developing conjugated materials as active components in flexible optoelectronics. The molecular packing and interaction topology of eight crystal systems of dicyano-distyrylbenzene derivatives are investigated. Face-to-face π-stacks in an inclined orientation relative to the bending surface can accommodate expansion and compression with minimal molecular motion from their equilibrium positions. This configuration exhibits good compliance towards mechanical strain, while a similar structure with a criss-cross arrangement capable of distributing applied strain equally in opposite directions enhances the flexibility. Molecular arrangements that cannot reversibly undergo expansion and compression exhibit brittleness. In the isometric CT crystals, the disproportionate strength of the interactions along the bending plane and orthogonal directions makes these materials sustain a moderate bending strain. These results provide an updated explanation for the elastic bending in semiconducting π-conjugated crystals.
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Ambipolar field-effect transistors (FETs) possessing both electron and hole carriers enable implementation of novel reconfigurable transistors, artificial synaptic transistors, and output polarity controllable (OPC) amplifiers. Here, we fabricated a two-dimensional (2D) material-based complementary ambipolar FET and investigated its electrical characteristics. Properties of ohmic-like contacts at source/drain sides were verified from output characteristics and temperature-dependent measurements. The symmetry of electron and hole currents can be easily achieved by optimization of the MoS2or WSe2channels, different from the conventional ambipolar FET with fundamental issues related to Schottky barriers. In addition, we demonstrated successful operation of a complementary inverter and OPC amplifier, using the fabricated complementary ambipolar FET based on 2D materials.
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Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin-modifying proteins may be a conserved mechanism of aging in eukaryotes.
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Envejecimiento/genética , Cromatina/metabolismo , Inestabilidad Genómica , Sirtuinas/genética , Animales , Encéfalo/metabolismo , Línea Celular Tumoral , Roturas del ADN de Doble Cadena , Reparación del ADN , Células Madre Embrionarias , Técnicas de Inactivación de Genes , Humanos , Linfoma/metabolismo , Ratones , Datos de Secuencia Molecular , Estrés Oxidativo , Sirtuina 1 , Organismos Libres de Patógenos Específicos , Neoplasias del Timo/metabolismo , Levaduras/citología , Levaduras/metabolismoRESUMEN
BACKGROUND: Chronic subdural hematoma (cSDH) is a unique hemorrhagic complication associated with microsurgical clipping. We aimed to investigate the risk factors of subdural hygroma (SDG) formation and its hemorrhagic conversion to cSDH. METHODS: We reviewed the medical records of 229 patients who underwent microsurgical clipping for unruptured intracranial aneurysms (UIA) from 2016 to 2019. Risk factors for SDG and cSDH formation were analyzed. RESULTS: Male sex, age ≥ 60 years, higher degree of arachnoid dissection, severe brain atrophy, and a large volume of subdural fluid collection (SFC) before discharge were independent risk factors for SDG formation. The risk factors for hemorrhagic conversion from SDG were continuous use or early resumption of antiplatelet drugs (odds ratio (OR): 15.367, 95% CI: 1.172-201.402) and a larger volume of SFC before discharge (OR: 0.932, 95% CI: 0.886-0.980). In the early resumption group, antiplatelet drug was resumed at a mean duration of 7.48 days postoperatively, and hemorrhagic conversion was detected earlier than that in the late resumption or no-use groups (4.09 vs. 7.18 weeks, P = 0.046). Following the receiver operating characteristic analysis, the SFC cutoff volume for hemorrhagic conversion was determined to be 23.55 mL. CONCLUSION: These findings can assist clinicians in identifying patients at a high risk of SDG and cSDH formation. Antiplatelet resumption and its timing should be determined with consideration of the risk of cSDH formation as well as individual medical conditions.
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Hematoma Subdural Crónico , Aneurisma Intracraneal , Efusión Subdural , Humanos , Masculino , Persona de Mediana Edad , Aneurisma Intracraneal/cirugía , Aneurisma Intracraneal/complicaciones , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Hematoma Subdural Crónico/complicaciones , Factores de RiesgoRESUMEN
Recurrent aneurysms are a major cause of re-aneurysmal subarachnoid hemorrhage (aSAH), but information on long-term clip durability and predictors is insufficient. This study aimed to present the incidence rate of > 10 years and investigate predictors of a recurrent aneurysm in aSAH survivors. We included 1601 patients admitted with aSAH and treated by microsurgical clipping between January 1993 and May 2010. Of these patients, 435 aSAH survivors were included in this study (27.2%). The total follow-up time was 5680.9 patient-years, and the overall incidence rate was 0.77% per patient-year. The cumulative probability of recurrence without residua and regrowth of the neck remnant was 0.7% and 13.9% at 10 years, respectively. Neck remnant (hazard ratio [HR], 10.311; 95% confidence interval [CI], 5.233-20.313) and alcohol consumption over the moderate amount (HR, 3.166; 95% CI, 1.313-7.637) were independent risk factors of recurrent aneurysm. Current smoking and multiplicity at initial aSAH presentation were significant factors in a univariate analysis. Furthermore, de novo intracranial aneurysms (DNIAs) were more common in the recurrent group than in the non-recurrent group (40.9% vs. 11.5%, P < 0.001). In the present study, we noted the long-term clip durability and predictor of recurrence after microsurgical clipping. These findings can assist clinicians in identifying patients at a high risk of recurrent aneurysm and recommending selective long-term surveillance after microsurgical clipping.
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Aneurisma Intracraneal , Hemorragia Subaracnoidea , Estudios de Seguimiento , Humanos , Incidencia , Aneurisma Intracraneal/epidemiología , Aneurisma Intracraneal/etiología , Aneurisma Intracraneal/cirugía , Recurrencia , Estudios Retrospectivos , Hemorragia Subaracnoidea/epidemiología , Hemorragia Subaracnoidea/etiología , Hemorragia Subaracnoidea/cirugía , Sobrevivientes , Resultado del TratamientoRESUMEN
BACKGROUND: Severe intracranial atherosclerotic stenosis (ICAS) is a major cause of stroke. Although percutaneous transluminal angioplasty and stenting (PTAS) treatment methods have increased over the last decade as alternative therapies, there is debate regarding the best method of treatment, with medical and surgical therapies often suggested. METHODS: We analyzed the long-term follow-up results from 5 years of intracranial stenting for intracranial stenosis from three stroke centers. The primary endpoints were early stroke complications or death within 30 days after stent insertion, and the secondary endpoint was a recurrent stroke between 30 days and 60 months. Correlating factors and Kaplan-Meier survival curves for recurrent stroke and in-stent restenosis (ISR) were also obtained. RESULTS: Seventy-three PTAS in 71 patients were examined in this study. The primary and secondary endpoints were all 8.2% (n = 6), and restenosis was 13.7% (n = 10) during the 5-year follow-up. The primary endpoints were significantly frequent in the high National Institutes of Health Stroke Scale (NIHSS) and early stent (≤ 7 days after dual antiplatelet medication) groups. Secondary endpoint and ISR were identically frequent in the younger age group and in the presence of tandem stenosis in other major intracranial arteries. The cumulative probability of recurrent stroke and ISR at 60 months was 16.4% and 14.1%, respectively. CONCLUSIONS: This study shows that PTAS is safe and effective for major ICAS. Reducing the early complication rate is still an important factor, despite the fact that long-term stroke recurrence was low.
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Arteriosclerosis Intracraneal , Accidente Cerebrovascular , Angioplastia/efectos adversos , Constricción Patológica/diagnóstico por imagen , Constricción Patológica/cirugía , Humanos , Arteriosclerosis Intracraneal/diagnóstico por imagen , Arteriosclerosis Intracraneal/cirugía , Stents/efectos adversos , Accidente Cerebrovascular/etiología , Resultado del Tratamiento , Estados UnidosRESUMEN
BACKGROUND AND PURPOSE: The association between intracranial aneurysms (IAs) and Marfan syndrome (MFS) is controversial. We aimed to evaluate the prevalence and characteristics of IAs in patients with MFS using brain imaging and compare it with the general population. METHODS: Between 2007 and 2020, 118 patients with confirmed MFS who underwent brain imaging were enrolled and classified into 2 groups; IA group versus non-IA. Demographic data were acquired from their medical records, including age, sex, comorbidities, and aortic diseases. Two readers reviewed all brain images independently regarding the presence, morphology, size, and location of IAs. All data were compared between both groups, and IA characteristics in MFS were analyzed using a database of controls with IAs. RESULTS: The prevalence of IAs was 11.9% in patients with MFS. IA group were significantly older in age (44.6±12.1 years in IA versus 36.8±14.0 years in non-IA, P=0.039) and had female predominance (71.4% in IA versus 43.3% in non-IA, P=0.047). All IAs were unruptured, and there was no subarachnoid hemorrhage during the follow-up period (mean; 53.5±43.3 months). The mean diameter of IAs was significantly larger (4.23±1.80 mm in MFS versus 3.04±1.57 mm in control, P=0.004). IAs with MFS were frequently located in the vertebrobasilar artery (33.3% in MFS versus 2.1% in control, P=0.002) and more common in fusiform morphology (13.3% in MFS versus 1.1% in control, P=0.048). CONCLUSIONS: This large-cohort study demonstrated a high prevalence and differential features of IAs in MFS, which may support the association between IAs and MFS.
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Encéfalo/diagnóstico por imagen , Aneurisma Intracraneal/etiología , Síndrome de Marfan/complicaciones , Adulto , Anciano , Aneurisma Roto , Estudios de Cohortes , Angiografía por Tomografía Computarizada , Femenino , Estudios de Seguimiento , Humanos , Aneurisma Intracraneal/diagnóstico por imagen , Aneurisma Intracraneal/epidemiología , Angiografía por Resonancia Magnética , Masculino , Síndrome de Marfan/diagnóstico por imagen , Síndrome de Marfan/epidemiología , Persona de Mediana Edad , PrevalenciaRESUMEN
INTRODUCTION: Reports on patients' satisfaction and preferred characteristics for treatments would be worthwhile when choosing an optimal treatment reflecting patients' perspectives. AIM: To identify the characteristics and treatment patterns of patients with haemophilia A, or their caregivers, in Korea and explore patient preferences and satisfaction with their treatment. METHODS: This cross-sectional, multicentre, observational study was conducted from April 2018 to September 2019 at six nationwide hospitals and three Korea Hemophilia Foundation clinics. Patients aged ≥16 years, or legal caregivers of paediatric patients, who had used factor VIII (FVIII) concentrates for ≥1 month were enrolled. Satisfaction with treatment was measured using the Treatment Satisfaction Questionnaire for Medication (TSQM); preference was evaluated using discrete choice experiment (DCE), with 10 series of two hypothetical treatment options created from D-efficient block design, which varied across five attributes. RESULTS: Overall, 505 patients (mean age 31 years) were enrolled in the study. Patients had received FVIII concentrate for an average of 102.9 months (prophylaxis: 53.5%; on-demand: 22.2%). Mean TSQM scores were 64.6 (effectiveness domain), 97.9 (side effects), 57.1 (convenience) and 66.8 (global satisfaction). The number of vials per injection, and the frequency of drug administration, was significantly associated with treatment satisfaction. According to DCE, simpler treatment options were preferred by patients/caregivers. CONCLUSION: The lowest satisfaction levels were shown in the treatment convenience domain. Patients/parents preferred simpler and easier treatment characteristics. In an attempt to enhance the overall satisfaction of patients and caregivers with treatment, consideration of more convenient characteristics is required in future decisions regarding treatment selection.
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Hemofilia A , Niño , Estudios Transversales , Hemofilia A/tratamiento farmacológico , Humanos , Recién Nacido , Padres , Prioridad del Paciente , Satisfacción del Paciente , Satisfacción PersonalRESUMEN
BACKGROUND: Incidence, prevalence, and long-term survival outcomes in patients with moyamoya angiopathy (MMA) according to stroke presentation type and age group have not been clearly elucidated. METHODS: We investigated mortality in patients with MMA (moyamoya disease, probable moyamoya disease, moyamoya syndrome) of whose International Classification Disease 10 code was I67.5 from 2006 to 2015 using the Korean National Health Insurance database. MMA at diagnosis was classified into 3 types (ischemic, hemorrhagic, and asymptomatic or else) according to stroke presentation. Survival analysis was performed according to stroke presentation type and age group (< 15 years and ≥ 15 years) using the Kaplan-Meier method. RESULTS: There were 12,146 newly diagnosed moyamoya cases, with a female-to-male ratio of 1.81; the ischemic type was identified in 3671 (30.2%) patients, the hemorrhagic type in 2449 (20.2%) patients, and the asymptomatic or else type in 6026 (49.6%) patients. The mean age at diagnosis according to stroke presentation was 33.1 (± 14.8) years in asymptomatic or else type, 41.2 (± 17.3) years in ischemic type, and 45.4 (± 14.3) years in hemorrhagic type (P < 0.001). The 10-year survival rates in ischemic-, hemorrhagic-, and asymptomatic or else-type patients were 88.9%, 76.3%, and 94.3%, respectively (log-rank test; P < 0.001). Pediatric MMA (< 15 years) and adult MMA (≥ 15 years) showed different survival curves according to stroke presentation type (log-rank test; P = 0.017, P < 0.001, respectively). CONCLUSIONS: Our study showed that moyamoya patients had different diagnosis ages and distinct survival courses according to stroke presentation type. Adult moyamoya patients with hemorrhagic presentation had the worst survival outcomes.
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Enfermedad de Moyamoya , Accidente Cerebrovascular , Adolescente , Adulto , Niño , Femenino , Humanos , Incidencia , Masculino , Prevalencia , República de Corea/epidemiología , Accidente Cerebrovascular/diagnósticoRESUMEN
This corrects the article on p. e393 in vol. 35, PMID: 33258329.
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Molecular martensitic materials are an emerging class of smart materials with enormous tunability in physicochemical properties, attributed to the tailored molecular and crystal structures through molecular design. This class of materials exhibits ultrafast and reversible structural transitions in response to thermal and mechanical stimuli, which underlies fascinating properties such as thermoelasticity, superelasticity, ferroelasticity, and shape memory effect. These dynamic properties are not widely explored in molecular crystals and therefore molecular martensitic materials represent a new frontier in the field of solid-state chemistry. In martensitic transitions, the materials not only exhibit substantial shape changes but also remember the functions in the associated polymorphic phases. This suggests promising applicability towards light-weight actuators, lifts, dampers, sensors, shape-/function-memory and ultraflexible optoelectronic devices. In this article, we review characteristics, detailed transition mechanisms, and potential applications of molecular martensitic materials. In particular, we aim to describe transition characteristics by collecting cases with similar transition principles in order to glean insights into further advancement of molecular martensitic materials. Overall, we believe that molecular martensitic materials are emerging as the next generation smart materials that have shown promise in advancing a wide range of domains of applications.
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The anthelmintic drug praziquantel (PZQ) is used to treat schistosomiasis, a neglected tropical disease that affects over 200 million people worldwide. PZQ causes Ca2+ influx and spastic paralysis of adult worms and rapid vacuolization of the worm surface. However, the mechanism of action of PZQ remains unknown even after 40 years of clinical use. Here, we demonstrate that PZQ activates a schistosome transient receptor potential (TRP) channel, christened SmTRPMPZQ, present in parasitic schistosomes and other PZQ-sensitive parasites. Several properties of SmTRPMPZQ were consistent with known effects of PZQ on schistosomes, including (i) nanomolar sensitivity to PZQ; (ii) stereoselectivity toward (R)-PZQ; (iii) mediation of sustained Ca2+ signals in response to PZQ; and (iv) a pharmacological profile that mirrors the well-known effects of PZQ on muscle contraction and tegumental disruption. We anticipate that these findings will spur development of novel therapeutic interventions to manage schistosome infections and broader interest in PZQ, which is finally unmasked as a potent flatworm TRP channel activator.
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Antihelmínticos/farmacología , Praziquantel/farmacología , Schistosoma/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Animales , Electrofisiología , Femenino , Células HEK293 , Humanos , Ratones , Schistosoma/efectos de los fármacosRESUMEN
BACKGROUND: Oral propranolol has become first-line treatment for infantile hemangiomas (IHs). This study focused on identifying cytokines related to the biology of IH and early regression indicators of IH after propranolol treatment. METHODS: For inclusion, the patients had to be aged less than 1 year and have an IH with a largest diameter ≥2 cm. Patients were scheduled to receive 1 year of propranolol treatment. Serum cytokines involved in angiogenesis, vasculogenesis, and/or chronic inflammation were analyzed at 0, 1, and/or 12 months after treatment using Multiplex Luminex assays. RESULTS: Among the 49 evaluable patients, 33 completed the 1-year treatment: 16 showed excellent response and 12 had good response to propranolol. Significant decreases in serum MMP-2, bFGF, VEGF-α, and MCP-1 levels were observed after 1 year of treatment compared to pretreatment values. The maximal diameters of the lesions significantly correlated with pretreatment serum VEGF-α, bFGF, and MMP-9. Patients with higher bFGF and VEGF levels showed better response to propranolol at 1 year. CONCLUSION: MMP-2, VEGF-α, bFGF, and MCP-1 may involve in the biology of IH and their downregulation may be associated with involution processes of IH. Pretreatment bFGF and VEGF could be novel biomarkers for predicting response to propranolol. IMPACT: We found that decreases in the concentrations of MMP-2, bFGF, VEGF, and MCP-1 were associated with regression of the hemangioma, which indicates that one of the mechanisms of propranolol in the treatment of proliferative hemangiomas may involve downregulation of those cytokines. Patients with higher bFGF and VEGF levels showed better response to propranolol at 1 year. Importantly, serum bFGF higher than 37.07 pg/mL may predict an excellent response to propranolol. Therefore, along with the patient's age and the size and visual characteristics of the lesion, bFGF levels could help determine the viability of propranolol use in the treatment of IHs. Our study represented extensive serum profiling in IH, reporting the indicators and molecules clearly related to IH regression with propranolol treatment. The authors believe that monitoring serum cytokines, including MMP-2, bFGF, VEGF, and MCP-1, in IH patients could be important, in addition to clinical follow-up, for determining when to start and end propranolol treatment.
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Antagonistas Adrenérgicos beta/administración & dosificación , Antineoplásicos/administración & dosificación , Factor 2 de Crecimiento de Fibroblastos/sangre , Hemangioma/tratamiento farmacológico , Propranolol/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/sangre , Administración Oral , Antagonistas Adrenérgicos beta/efectos adversos , Antineoplásicos/efectos adversos , Biomarcadores de Tumor/sangre , Quimiocina CCL2/sangre , Femenino , Hemangioma/sangre , Hemangioma/diagnóstico , Humanos , Lactante , Recién Nacido , Masculino , Metaloproteinasa 2 de la Matriz/sangre , Valor Predictivo de las Pruebas , Propranolol/efectos adversos , Estudios Prospectivos , República de Corea , Factores de Tiempo , Resultado del TratamientoRESUMEN
Phosphatidylserine is one of the phospholipids present in cell membranes, especially in brain and nervous system. The phosphatidylserine content is reduced with aging and age-related decrease in phosphatidylserine is known to contribute to cognitive impairment and Alzheimer's disease in the elderly. In the present study, we examined the effect of supplementation with phosphatidylserine on the response to oxidative stress and aging using C. elegans as a model system. Dietary supplementation with phosphatidylserine significantly increased resistance to oxidative stress and extended lifespan accompanying reduced fertility as a trade-off. Age-related decline in motility was also delayed by supplementation with phosphatidylserine. The cellular levels of reactive oxygen species and the expression of stress-responsive genes were increased by phosphatidylserine treatment, suggesting a hormetic effect. The extension of lifespan by phosphatidylserine overlaps with reduced insulin/IGF-1-like signaling and requires DAF-16. The effect of phosphatidylserine on age-related diseases was examined using animal model of disease. Supplementation with phosphatidylserine significantly suppressed amyloid beta-induced toxicity in Alzheimer's disease model. Reduced survival in diabetes mellitus due to high-glucose diet was reversed by supplementation with phosphatidylserine. This study reports the anti-oxidative stress and anti-aging effect of phosphatidylserine for the first time at the organismal level and proposes possible underlying mechanisms.
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Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/efectos de los fármacos , Suplementos Dietéticos , Factores de Transcripción Forkhead/metabolismo , Hormesis , Longevidad/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Fosfatidilserinas/administración & dosificación , Factores de Edad , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Factores de Transcripción Forkhead/genética , Movimiento/efectos de los fármacos , Fosfatidilserinas/metabolismoRESUMEN
Acute lymphoblastic leukemia (ALL) with hyperleukocytosis at diagnosis is associated with early morbidity and mortality due to complications of leukostasis. Of 535 pediatric ALL patients (January 2004 to December 2016 from the Yeungnam region of Korea), 72 (13.5%) patients with an initial white blood cell (WBC) count of ≥100×10/L were included in this study, of whom 38 patients had extreme hyperleukocytosis (WBC>200×10/L) at diagnosis. Fourteen patients (19.4%) had ≥1 early respiratory and neurologic complications during induction therapy. Relapse occurred in 8 patients (24.2%) with extreme hyperleukocytosis and in 1 patient (3.0%) with an initial WBC count of 100 to 200×10/L (P=0.012). Estimated 10-year event-free survival rate (EFS) and overall survival rate were 78.3%±8.4% and 82.6%±7.7%, respectively. The 10-year EFS was significantly lower in patients with an initial WBC count of >200×10/L than in those with an initial WBC count of 100 to 200×10/L (65.7%±13.4% vs. 91.2%±7.9%; P=0.011). The 10-year EFS and overall survival rate did not differ significantly between patients with extreme hyperleukocytosis who received hematopoietic stem cell transplantation and those who received chemotherapy. In conclusion, pediatric ALL with hyperleukocytosis can lead to early complications and mortality. Patients with initial extreme hyperleukocytosis showed significantly poorer prognosis than those with WBC counts of 100 to 200×10/L.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucocitosis , Leucemia-Linfoma Linfoblástico de Células Precursoras , Aloinjertos , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Recuento de Leucocitos , Leucocitosis/sangre , Leucocitosis/diagnóstico , Leucocitosis/mortalidad , Leucocitosis/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recurrencia , República de Corea/epidemiología , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Hereditary hemolytic anemia (HHA) is a rare disease characterized by premature red blood cell (RBC) destruction due to intrinsic RBC defects. The RBC Disorder Working Party of the Korean Society of Hematology established and updated the standard operating procedure for making an accurate diagnosis of HHA since 2007. The aim of this study was to investigate a nationwide epidemiology of Korean HHA. METHODS: We collected the data of a newly diagnosed pediatric HHA cohort (2007-2016) and compared this cohort's characteristics with those of a previously surveyed pediatric HHA cohort (1997-2006) in Korea. Each participant's information was retrospectively collected by a questionnaire survey. RESULTS: A total of 369 children with HHA from 38 hospitals distributed in 16 of 17 districts of Korea were investigated. RBC membranopathies, hemoglobinopathies, RBC enzymopathies, and unknown etiologies accounted for 263 (71.3%), 59 (16.0%), 23 (6.2%), and 24 (6.5%) of the cases, respectively. Compared to the cohort from the previous decade, the proportions of hemoglobinopathies and RBC enzymopathies significantly increased (P < 0.001 and P = 0.008, respectively). Twenty-three of the 59 hemoglobinopathy patients had immigrant mothers, mostly from South-East Asia. CONCLUSION: In Korea, thalassemia traits have increased over the past 10 years, reflecting both increased awareness of this disease and increased international marriages. The enhanced recognition of RBC enzymopathies is due to advances in diagnostic technique; however, 6.5% of HHA patients still do not have a clear diagnosis. It is necessary to improve accessibility of diagnosing HHA.
Asunto(s)
Anemia Hemolítica Congénita/epidemiología , Adolescente , Anemia Hemolítica Congénita/diagnóstico , Anemia Hemolítica Congénita no Esferocítica/diagnóstico , Anemia Hemolítica Congénita no Esferocítica/epidemiología , Niño , Preescolar , Femenino , Deficiencia de Glucosafosfato Deshidrogenasa/diagnóstico , Deficiencia de Glucosafosfato Deshidrogenasa/epidemiología , Hemoglobinopatías/diagnóstico , Hemoglobinopatías/epidemiología , Hemoglobinas/genética , Hospitales , Humanos , Lactante , Recién Nacido , Masculino , Polimorfismo Genético , Piruvato Quinasa/deficiencia , Errores Innatos del Metabolismo del Piruvato/diagnóstico , Errores Innatos del Metabolismo del Piruvato/epidemiología , República de Corea/epidemiología , Estudios Retrospectivos , Encuestas y CuestionariosRESUMEN
BACKGROUND: Hodgkin's lymphoma (HL) constitutes 10%-20% of all malignant lymphomas and has a high cure rate (5-year survival, around 90%). Recently, interest has increased concerning preventing secondary complications (secondary cancer, endocrine disorders) in long-term survivors. We aimed to study the epidemiologic features and therapeutic outcomes of HL in children, adolescents, and young adults in Korea. METHODS: We performed a multicenter, retrospective study of 224 patients aged < 25 years diagnosed with HL at 22 participating institutes in Korea from January 2007 to August 2016. RESULTS: A higher percentage of males was diagnosed at a younger age. Nodular sclerosis histopathological HL subtype was most common, followed by mixed cellularity subtype. Eighty-one (36.2%), 101 (45.1%), and 42 (18.8%) patients were classified into low, intermediate, and high-risk groups, respectively. Doxorubicin, bleomycin, vinblastine, dacarbazine was the most common protocol (n = 102, 45.5%). Event-free survival rate was 86.0% ± 2.4%, while five-year overall survival (OS) rate was 96.1% ± 1.4%: 98.7% ± 1.3%, 97.7% ± 1.6%, and 86.5% ± 5.6% in the low, intermediate, and high-risk groups, respectively (P = 0.021). Five-year OS was worse in patients with B-symptoms, stage IV disease, high-risk, splenic involvement, extra-nodal lymphoma, and elevated lactate dehydrogenase level. In multivariate analysis, B-symptoms and extra-nodal involvement were prognostic factors for poor OS. Late complications of endocrine disorders and secondary malignancy were observed in 17 and 6 patients, respectively. CONCLUSION: This is the first study on the epidemiology and treatment outcomes of HL in children, adolescents, and young adults in Korea. Future prospective studies are indicated to develop therapies that minimize treatment toxicity while maximizing cure rates in children, adolescents, and young adults with HL.