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Although treatment of multiple myeloma (MM) with daratumumab significantly extends the patient's lifespan, resistance to therapy is inevitable. ISB 1342 was designed to target MM cells from patients with relapsed/refractory MM (r/r MM) displaying lower sensitivity to daratumumab. ISB 1342 is a bispecific antibody with a high-affinity Fab binding to CD38 on tumor cells on a different epitope than daratumumab and a detuned scFv domain affinity binding to CD3ε on T cells, to mitigate the risk of life-threatening cytokine release syndrome, using the Bispecific Engagement by Antibodies based on the TCR (BEAT) platform. In vitro, ISB 1342 efficiently killed cell lines with different levels of CD38, including those with a lower sensitivity to daratumumab. In a killing assay where multiple modes of action were enabled, ISB 1342 showed higher cytotoxicity toward MM cells compared with daratumumab. This activity was retained when used in sequential or concomitant combinations with daratumumab. The efficacy of ISB 1342 was maintained in daratumumab-treated bone marrow patient samples showing lower sensitivity to daratumumab. ISB 1342 induced complete tumor control in 2 therapeutic mouse models, unlike daratumumab. Finally, in cynomolgus monkeys, ISB 1342 displayed an acceptable toxicology profile. These data suggest that ISB 1342 may be an option in patients with r/r MM refractory to prior anti-CD38 bivalent monoclonal antibody therapies. It is currently being developed in a phase 1 clinical study.
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Anticuerpos Biespecíficos , Mieloma Múltiple , Animales , Ratones , ADP-Ribosil Ciclasa 1/metabolismo , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Linfocitos T/patologíaRESUMEN
BACKGROUND: The initiation of migraine headaches and the involvement of neuroinflammatory signaling between parenchymal and meningeal cells remain unclear. Experimental evidence suggests that a cascade of inflammatory signaling originating from neurons may extend to the meninges, thereby inducing neurogenic inflammation and headache. This review explores the role of parenchymal inflammatory signaling in migraine headaches, drawing upon recent advancements. BODY: Studies in rodents have demonstrated that sterile meningeal inflammation can stimulate and sensitize meningeal nociceptors, culminating in headaches. The efficacy of relatively blood-brain barrier-impermeable anti-calcitonin gene-related peptide antibodies and triptans in treating migraine attacks, both with and without aura, supports the concept of migraine pain originating in meninges. Additionally, PET studies utilizing inflammation markers have revealed meningeal inflammatory activity in patients experiencing migraine with aura, particularly over the occipital cortex generating visual auras. The parenchymal neuroinflammatory signaling involving neurons, astrocytes, and microglia, which eventually extends to the meninges, can link non-homeostatic perturbations in the insensate brain to pain-sensitive meninges. Recent experimental research has brought deeper insight into parenchymal signaling mechanisms: Neuronal pannexin-1 channels act as stress sensors, initiating the inflammatory signaling by inflammasome formation and high-mobility group box-1 release in response to transient perturbations such as cortical spreading depolarization (CSD) or synaptic metabolic insufficiency caused by transcriptional changes induced by migraine triggers like sleep deprivation and stress. After a single CSD, astrocytes respond by upregulating the transcription of proinflammatory enzymes and mediators, while microglia are involved in restoring neuronal structural integrity; however, repeated CSDs may prompt microglia to adopt a pro-inflammatory state. Transcriptional changes from pro- to anti-inflammatory within 24 h may serve to dampen the inflammatory signaling. The extensive coverage of brain surface and perivascular areas by astrocyte endfeet suggests their role as an interface for transporting inflammatory mediators to the cerebrospinal fluid to contribute to meningeal nociception. CONCLUSION: We propose that neuronal stress induced by CSD or synaptic activity-energy mismatch may initiate a parenchymal inflammatory signaling cascade, transmitted to the meninges, thereby triggering lasting headaches characteristic of migraine, with or without aura. This neuroinflammatory interplay between parenchymal and meningeal cells points to the potential for novel targets for migraine treatment and prophylaxis.
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Meninges , Trastornos Migrañosos , Enfermedades Neuroinflamatorias , Transducción de Señal , Humanos , Trastornos Migrañosos/metabolismo , Trastornos Migrañosos/fisiopatología , Enfermedades Neuroinflamatorias/fisiopatología , Animales , Transducción de Señal/fisiología , Neuronas/metabolismoRESUMEN
Androgen receptor (AR) splice variants are proposed to be a potential driver of lethal castration-resistant prostate cancer. AR splice variant 7 (ARv7) is the most commonly observed isoform and strongly correlates with resistance to second-generation anti-androgens. Despite this clinical evidence, the interplay between ARv7 and the highly expressed full-length AR (ARfl) remains unclear. In this work, we show that ARfl/ARv7 heterodimers readily form in the nucleus via an intermolecular N/C interaction that brings the four termini of the proteins in close proximity. Combining fluorescence resonance energy transfer and fluorescence recovery after photobleaching, we demonstrate that these heterodimers undergo conformational changes following DNA binding, indicating dynamic nuclear receptor interaction. Although transcriptionally active, ARv7 can only form short-term interactions with DNA at highly accessible high-occupancy ARfl binding sites. Dimerization with ARfl does not affect ARv7 binding dynamics, suggesting that DNA binding occupancy is determined by the individual protein monomers and not the homodimer or heterodimer complex. Overall, these biophysical studies reveal detailed properties of ARv7 dynamics as both a homodimer or heterodimer with ARfl.
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Neoplasias de la Próstata Resistentes a la Castración , Línea Celular Tumoral , Humanos , Masculino , Isoformas de Proteínas , Receptores Androgénicos/genéticaRESUMEN
The role of high mobility group box 1 (HMGB1) in inflammation is well characterized in the immune system and in response to tissue injury. More recently, HMGB1 was also shown to initiate an "inflammatory signaling cascade" in the brain parenchyma after a mild and brief disturbance, such as cortical spreading depolarization (CSD), leading to headache. Despite substantial evidence implying a role for inflammatory signaling in prevalent neuropsychiatric disorders such as migraine and depression, how HMGB1 is released from healthy neurons and how inflammatory signaling is initiated in the absence of apparent cell injury are not well characterized. We triggered a single cortical spreading depolarization by optogenetic stimulation or pinprick in naïve Swiss albino or transgenic Thy1-ChR2-YFP and hGFAP-GFP adult mice. We evaluated HMGB1 release in brain tissue sections prepared from these mice by immunofluorescent labeling and immunoelectron microscopy. EzColocalization and Costes thresholding algorithms were used to assess the colocalization of small extracellular vesicles (sEVs) carrying HMGB1 with astrocyte or microglia processes. sEVs were also isolated from the brain after CSD, and neuron-derived sEVs were captured by CD171 (L1CAM). sEVs were characterized with flow cytometry, scanning electron microscopy, nanoparticle tracking analysis, and Western blotting. We found that HMGB1 is released mainly within sEVs from the soma of stressed neurons, which are taken up by surrounding astrocyte processes. This creates conditions for selective communication between neurons and astrocytes bypassing microglia, as evidenced by activation of the proinflammatory transcription factor NF-ĸB p65 in astrocytes but not in microglia. Transmission immunoelectron microscopy data illustrated that HMGB1 was incorporated into sEVs through endosomal mechanisms. In conclusion, proinflammatory mediators released within sEVs can induce cell-specific inflammatory signaling in the brain without activating transmembrane receptors on other cells and causing overt inflammation.
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Astrocitos , Proteína HMGB1 , Animales , Ratones , Astrocitos/metabolismo , Proteína HMGB1/metabolismo , Inflamación/etiología , Neuronas/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Self-medication refers to taking medicine without consultation with a doctor or dentist, and it is an important health issue, especially during the COVID-19 pandemic. There are no data about parents' SM practices for their children's dental problems during the COVID-19 pandemic. The present study aims to evaluate parents' knowledge, attitudes, and practices regarding self-medication for their children's dental problems during the COVID-19 pandemic in Northern Turkey. METHODS: A cross-sectional survey was carried out in the pediatric dental clinic at Ondokuz Mayis University, Faculty of Dentistry, Department of Pediatric Dentistry, immediately after the COVID-19 lockdown ended. A total of 389 parents who agreed to participate in the study completed the questionnaire from July 1 to October 1. A questionnaire with 18 items was designed to collect information on the parents' knowledge and attitudes regarding when, why, and how to use drugs and on their practices on medicating their children. The collected data were analyzed using descriptive and analytical statistics (chi-square test). RESULTS: The majority of parents (n = 273; 70.2%) practiced self-medication for their children's dental problems. Self-medication with a previously prescribed medications was usually preferred by parents (n = 179; 62.2%). Analgesics (98%) were the most commonly used medicines by parents in their self-medication for their children's dental problems. CONCLUSION: Prevalence of self-medication practices for children's dental problems is high in Turkey during the COVID-19 pandemic. Therefore, new healthcare services, such as teledentistry, may be useful to overcome problems related to the self-medication of children during times when the ability to reach healthcare providers is limited, such as during pandemics.
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COVID-19 , Pandemias , Niño , Control de Enfermedades Transmisibles , Estudios Transversales , Conocimientos, Actitudes y Práctica en Salud , Humanos , Padres , SARS-CoV-2 , Encuestas y Cuestionarios , Turquía/epidemiologíaRESUMEN
BACKGROUND: Pain is generally concomitant with an inflammatory reaction at the site where the nociceptive fibers are activated. Rodent studies suggest that a sterile meningeal inflammatory signaling cascade may play a role in migraine headache as well. Experimental studies also suggest that a parenchymal inflammatory signaling cascade may report the non-homeostatic conditions in brain to the meninges to induce headache. However, how these signaling mechanisms function in patients is unclear and debated. Our aim is to discuss the role of inflammatory signaling in migraine pathophysiology in light of recent developments. BODY: Rodent studies suggest that a sterile meningeal inflammatory reaction can be initiated by release of peptides from active trigeminocervical C-fibers and stimulation of resident macrophages and dendritic/mast cells. This inflammatory reaction might be needed for sustained stimulation and sensitization of meningeal nociceptors after initial activation along with ganglionic and central mechanisms. Most migraines likely have cerebral origin as suggested by prodromal neurologic symptoms. Based on rodent studies, a parenchymal inflammatory signaling cascade has been proposed as a potential mechanism linking cortical spreading depolarization (CSD) to meningeal nociception. A recent PET/MRI study using a sensitive inflammation marker showed the presence of meningeal inflammatory activity in migraine with aura patients over the occipital cortex generating the visual aura. These studies also suggest the presence of a parenchymal inflammatory activity, supporting the experimental findings. In rodents, parenchymal inflammatory signaling has also been shown to be activated by migraine triggers such as sleep deprivation without requiring a CSD because of the resultant transcriptional changes, predisposing to inadequate synaptic energy supply during intense excitatory transmission. Thus, it may be hypothesized that neuronal stress created by either CSD or synaptic activity-energy mismatch could both initiate a parenchymal inflammatory signaling cascade, propagating to the meninges, where it is converted to a lasting headache with or without aura. CONCLUSION: Experimental studies in animals and emerging imaging findings from patients warrant further research to gain deeper insight to the complex role of inflammatory signaling in headache generation in migraine.
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Depresión de Propagación Cortical , Trastornos Migrañosos , Animales , Humanos , Meninges , Trastornos Migrañosos/complicaciones , Inflamación Neurogénica , NociceptoresRESUMEN
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion mutations in the ATXN2 gene, mainly affecting motor neurons in the spinal cord and Purkinje neurons in the cerebellum. While the large expansions were shown to cause SCA2, the intermediate length expansions lead to increased risk for several atrophic processes including amyotrophic lateral sclerosis and Parkinson variants, e.g. progressive supranuclear palsy. Intense efforts to pioneer a neuroprotective therapy for SCA2 require longitudinal monitoring of patients and identification of crucial molecular pathways. The ataxin-2 (ATXN2) protein is mainly involved in RNA translation control and regulation of nutrient metabolism during stress periods. The preferential mRNA targets of ATXN2 are yet to be determined. In order to understand the molecular disease mechanism throughout different prognostic stages, we generated an Atxn2-CAG100-knock-in (KIN) mouse model of SCA2 with intact murine ATXN2 expression regulation. Its characterization revealed somatic mosaicism of the expansion, with shortened lifespan, a progressive spatio-temporal pattern of pathology with subsequent phenotypes, and anomalies of brain metabolites such as N-acetylaspartate (NAA), all of which mirror faithfully the findings in SCA2 patients. Novel molecular analyses from stages before the onset of motor deficits revealed a strong selective effect of ATXN2 on Nat8l mRNA which encodes the enzyme responsible for NAA synthesis. This metabolite is a prominent energy store of the brain and a well-established marker for neuronal health. Overall, we present a novel authentic rodent model of SCA2, where in vivo magnetic resonance imaging was feasible to monitor progression and where the definition of earliest transcriptional abnormalities was possible. We believe that this model will not only reveal crucial insights regarding the pathomechanism of SCA2 and other ATXN2-associated disorders, but will also aid in developing gene-targeted therapies and disease prevention.
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Acetiltransferasas/genética , Ácido Aspártico/análogos & derivados , Ataxina-2/genética , Técnicas de Sustitución del Gen/métodos , Ataxias Espinocerebelosas/genética , Repeticiones de Trinucleótidos/genética , Acetiltransferasas/biosíntesis , Animales , Ácido Aspártico/genética , Ácido Aspártico/metabolismo , Ataxina-2/biosíntesis , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Masculino , Ratones , Ratones Transgénicos , Ataxias Espinocerebelosas/metabolismo , Ataxias Espinocerebelosas/patologíaRESUMEN
Ataxin-2 (human gene symbol ATXN2) acts during stress responses, modulating mRNA translation and nutrient metabolism. Ataxin-2 knockout mice exhibit progressive obesity, dyslipidemia, and insulin resistance. Conversely, the progressive ATXN2 gain of function due to the fact of polyglutamine (polyQ) expansions leads to a dominantly inherited neurodegenerative process named spinocerebellar ataxia type 2 (SCA2) with early adipose tissue loss and late muscle atrophy. We tried to understand lipid dysregulation in a SCA2 patient brain and in an authentic mouse model. Thin layer chromatography of a patient cerebellum was compared to the lipid metabolome of Atxn2-CAG100-Knockin (KIN) mouse spinocerebellar tissue. The human pathology caused deficits of sulfatide, galactosylceramide, cholesterol, C22/24-sphingomyelin, and gangliosides GM1a/GD1b despite quite normal levels of C18-sphingomyelin. Cerebellum and spinal cord from the KIN mouse showed a consistent decrease of various ceramides with a significant elevation of sphingosine in the more severely affected spinal cord. Deficiency of C24/26-sphingomyelins contrasted with excess C18/20-sphingomyelin. Spinocerebellar expression profiling revealed consistent reductions of CERS protein isoforms, Sptlc2 and Smpd3, but upregulation of Cers2 mRNA, as prominent anomalies in the ceramide-sphingosine metabolism. Reduction of Asah2 mRNA correlated to deficient S1P levels. In addition, downregulations for the elongase Elovl1, Elovl4, Elovl5 mRNAs and ELOVL4 protein explain the deficit of very long-chain sphingomyelin. Reduced ASMase protein levels correlated to the accumulation of long-chain sphingomyelin. Overall, a deficit of myelin lipids was prominent in SCA2 nervous tissue at prefinal stage and not compensated by transcriptional adaptation of several metabolic enzymes. Myelination is controlled by mTORC1 signals; thus, our human and murine observations are in agreement with the known role of ATXN2 yeast, nematode, and mouse orthologs as mTORC1 inhibitors and autophagy promoters.
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Ataxina-2/genética , Ceramidas/metabolismo , Esfingomielinas/metabolismo , Ataxias Espinocerebelosas/genética , Expansión de Repetición de Trinucleótido/genética , Animales , Ataxina-2/metabolismo , Modelos Animales de Enfermedad , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Humanos , Metabolismo de los Lípidos/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Noqueados , Esfingomielina Fosfodiesterasa/genética , Esfingomielina Fosfodiesterasa/metabolismo , Esfingosina N-Aciltransferasa/genética , Esfingosina N-Aciltransferasa/metabolismo , Ataxias Espinocerebelosas/metabolismo , Ataxias Espinocerebelosas/patologíaRESUMEN
Antibodies play an important role in combating and controlling viral diseases such as influenza. Immunoglobulin Y (IgY) antibodies have several advantages such as a less invasive manufacturing process, ease of isolation, higher affinity compared with IgG antibodies, and cost-effectiveness. To date, although specific IgY production has been performed for different strains of influenza A, to the best of our knowledge, an IgY against the M2e peptide has not been produced. In the current study, IgY antibodies are produced, purified, and characterized using the M2e peptide sequence for the first time with the intent to apply them for the diagnosis of influenza A virus. Anti-M2e IgY antibodies are obtained from eggs using a two-step purification method. The activity and characterization of the antibodies are determined using an enzyme-linked immunosorbent assay, a nano-spectrophotometer, an SDS-Page assay, and a Western Blot analysis. Finally, anti-M2e IgY antibodies are conjugated to the latex nanoparticles, and the reaction between the influenza A virus and the nanoparticles is demonstrated using light microscopy, transmission electron microscopy, and energy dispersive X-ray spectroscopy. In conclusion, this study shows that anti-M2e IgY antibodies can contribute to the diagnosis, treatment, and prevention of the influenza A virus.
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Anticuerpos Antivirales , Pollos/inmunología , Inmunoglobulinas , Subtipo H1N1 del Virus de la Influenza A , Gripe Aviar/diagnóstico , Nanopartículas/química , Péptidos/inmunología , Proteínas Virales/inmunología , Animales , Anticuerpos Antivirales/química , Anticuerpos Antivirales/inmunología , Especificidad de Anticuerpos , Inmunoglobulinas/química , Inmunoglobulinas/inmunología , Subtipo H1N1 del Virus de la Influenza A/química , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Aviar/inmunología , Péptidos/química , Proteínas Virales/químicaRESUMEN
Molecularly imprinted polymers (MIPs) are artificial receptors which can be tailored to bind target molecules specifically. A new method, using photoinitiated atom-transfer radical polymerization (ATRP) for their synthesis as monoliths, thin films and nanoparticles is described. The synthesis takes place at room temperature and is compatible with acidic monomers, two major limitations for the use of ATRP with MIPs. The method has been validated with MIPs specific for the drugs testosterone and S-propranolol. This study considerably widens the range of functional monomers and thus molecular templates which can be used when MIPs are synthesized by ATRP, as well as the range of physical forms of these antibody mimics, in particular films and lithographic patterns, and their post-functionalization from living chain-ends.
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OBJECTIVE: We aimed to evaluate acute kidney injury (AKI), occurrence of recovery and risk factors associated with permanent kidney injury and mortality in the elderly individuals. DESIGN: Evidence for this study was obtained from retrospective cohort study from our center. PATIENTS: A total of 193 patients (>65 years, mean age: 79.99 ± 6.93) with acute kidney injury were enrolled in this study between 2011 and 2012. PATIENTS with kidney failure or renal replacement therapy (RRT) history at admission were excluded. INTERVENTION: Main outcome measurements: serum creatinine (SCr), estimated GFR (with CKD-Epi) and complete blood counts were evaluated at baseline and daily basis thereafter. The AKI was defined based on Kidney Disease Improving Global Outcomes (KDIGO) classification. RESULTS: Among 193 patients, 43 (22%) patients required RRT. Mortality rate was 18% (n = 36) SCr levels were restored within 9.9 ± 6.7days on average (8-39 days). Sixteen patients (12.7%) required RRT after discharge. The mean hospital stay was 10.1 ± 8.6 days (7-41 days). Mortality rate of patients who have no renal recovery was higher (44.8% vs. 4.8%) than renal recovery group (p < 0.01). CONCLUSION: The AKI represents a frequent complication in the elderly patients with longer hospital stay and increased mortality and morbidity. Our results show that dialytic support requirement is an independent predictor of permeant kidney injury in the elderly AKI patients. Older age, low diastolic blood pressure, high CRP and low hemoglobin levels were independent risk factors for mortality.
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Lesión Renal Aguda/terapia , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Hospitalización , Humanos , Masculino , Recuperación de la Función , Terapia de Reemplazo Renal , Estudios Retrospectivos , Factores de RiesgoRESUMEN
In patients with coronavirus disease (COVID-19), a massive inflammatory response is a significant cause of morbidity and mortality. Inflammatory markers are prognostic indicators of disease severity and the ultimate clinical outcome. Several studies have demonstrated a correlation between serum levels of neopterin, which can be an immune system marker, disease severity, and poor outcomes in COVID-19 patients. Our study aimed to determine the diagnostic significance of neopterin in conjunction with routinely measured inflammatory markers in patients with severe COVID-19. Serum neopterin, C-reactive protein (CRP), albumin levels, and complete blood count were determined in 39 patients with severe COVID-19 and 30 healthy individuals. Demographic characteristics, serum neopterin levels, and other laboratory data were compared between patients and healthy volunteers and statistically analyzed. High neopterin levels were observed in patients with severe COVID-19 compared to healthy volunteers. Furthermore, albumin levels were decreased, while CRP levels were increased in patients, statistically significantly. Also, positive correlations were shown between serum neopterin levels and serum CRP levels, while negative correlations were shown between serum neopterin levels and serum albumin levels. Systemic inflammation markers, CRP/albumin ratio, neutrophil/lymphocyte ratio, and platelet/lymphocyte ratio were significantly higher, while lymphocyte/monocyte ratio was also significantly lower in patients with severe COVID-19 than in healthy volunteers. However, serum neopterin levels were not linked to the CRP/albumin ratio, the neutrophil/lymphocyte ratio, or the platelet/lymphocyte ratio. On the other hand, they were linked negatively to the lymphocyte/monocyte ratio. Our findings highlight the association between high neopterin levels and patients with severe COVID-19. Neopterin is correlated with traditional inflammatory biomarkers and may indicate general immune and inflammatory activation in patients with severe COVID-19.
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Biomarcadores , Proteína C-Reactiva , COVID-19 , Neopterin , Índice de Severidad de la Enfermedad , Humanos , Neopterin/sangre , COVID-19/sangre , COVID-19/inmunología , Masculino , Femenino , Persona de Mediana Edad , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Proteína C-Reactiva/metabolismo , Adulto , SARS-CoV-2 , Anciano , Albúmina Sérica/análisisRESUMEN
Transient global amnesia (TGA) is characterized by isolated sudden anterograde amnesia. Diffusion restriction can be observed in the hippocampus on DWI-MRI at varying rates in TGA patients. This study analyzes the prevalence and characteristics of the hippocampal diffusion restriction (HDR), its relationship with vascular risk factors, and the prevalence of lesions overlooked in routine reports. 91 patients diagnosed with TGA at a tertiary hospital between 2011 and 2022 were evaluated retrospectively. The mean age was 64.8 ± 7.3 years, and 63.7% of patients were female. 75.8% of the patients had at least one vascular risk factor. Focal diffusion restriction was detected in 17 patients (18.5%) on DWI-MRI, with only one being extra-hippocampal. 81.2% of HDR was detected when DWI-MRI scan was performed between 12 and 96 h after the onset of symptoms. HDR was detected most when the imaging was performed in 24 to 48 h (p = 0.03). There was no correlation between the duration of symptoms and the detection rates of HDR (p = 0.55). In 9 patients (53% of 17) diffusion restriction was not specified in routine radiology reports. Although focal ischemia, venous flow abnormalities, migraine and epileptic phenomena have been suggested in its etiology, TGA is a clinical condition of which pathophysiology has not been determined clearly. Signal changes observed in DWI-MRI has led to discussions that cerebrovascular etiology may play a role, yet more comprehensive studies are required to prevent and manage TGA. HDRs can be overlooked in routine reports. Therefore, the DWI-MRI images of patients with TGA should be examined vigilantly.
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Amnesia Global Transitoria , Imagen de Difusión por Resonancia Magnética , Hipocampo , Humanos , Femenino , Amnesia Global Transitoria/diagnóstico por imagen , Amnesia Global Transitoria/etiología , Masculino , Persona de Mediana Edad , Hipocampo/diagnóstico por imagen , Anciano , Estudios Retrospectivos , Imagen de Difusión por Resonancia Magnética/métodosRESUMEN
In the quest to unravel the mysteries of neurological diseases, comprehending the underlying mechanisms is supreme. The SH-SY5Y human neuroblastoma cell line serves as a crucial tool in this endeavor; however, the cells are known for its sensitivity and slow proliferation rates. Typically, this cell line is cultured with 10% Fetal Bovine Serum (FBS) supplement. Nu-Serum (NuS), a low-protein alternative to FBS, is promising to advance cell culture practices. Herein, we evaluated the substitution of NuS for FBS to test the hypothesis that an alternative serum supplement can aid and promote SH-SY5Y cell proliferation and differentiation. Our findings revealed that the NuS-supplemented group exhibited a notable increase in adhered cells compared to both the FBS and serum-free (SF) groups. Importantly, cell viability remained high in both sera treated groups, with the NuS-supplemented cells displaying significantly larger cell sizes compared to the SF-treated group. Furthermore, cell proliferation rates were higher in the NuS-treated group, and neuroblast-like morphology was observed earlier than FBS group. Notably, both FBS and NuS supported the differentiation of these cells into mature neurons. Our data supports NuS as an alternative for SH-SY5Y cell culture, with the potential to elevate the quality of research in the neuroscience field.
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Neuroblastoma , Humanos , Neuroblastoma/metabolismo , Técnicas de Cultivo de Célula , Línea Celular , Diferenciación Celular , Proliferación Celular , Medios de Cultivo/farmacologíaRESUMEN
BACKGROUND: Extension of prostate cancer beyond the primary site by local invasion or nodal metastasis is associated with poor prognosis. Despite significant research on tumour evolution in prostate cancer metastasis, the emergence and evolution of cancer clones at this early stage of expansion and spread are poorly understood. We aimed to delineate the routes of evolution and cancer spread within the prostate and to seminal vesicles and lymph nodes, linking these to histological features that are used in diagnostic risk stratification. METHODS: We performed whole-genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and lymph nodes of five treatment-naive patients with locally advanced disease. We spatially mapped the clonal composition of cancer across the prostate and the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes in each individual by analysing a total of > 19,000 copy number corrected single nucleotide variants. RESULTS: In each patient, we identified sample locations corresponding to the earliest part of the malignancy. In patient 10, we mapped the spread of cancer from the apex of the prostate to the seminal vesicles and identified specific genomic changes associated with the transformation of adenocarcinoma to amphicrine morphology during this spread. Furthermore, we show that the lymph node metastases in this patient arose from specific cancer clones found at the base of the prostate and the seminal vesicles. In patient 15, we observed increased mutational burden, altered mutational signatures and histological changes associated with whole genome duplication. In all patients in whom histological heterogeneity was observed (4/5), we found that the distinct morphologies were located on separate branches of their respective evolutionary trees. CONCLUSIONS: Our results link histological transformation with specific genomic alterations and phylogenetic branching. These findings have implications for diagnosis and risk stratification, in addition to providing a rationale for further studies to characterise the genetic changes causally linked to morphological transformation. Our study demonstrates the value of integrating multi-region sequencing with histopathological data to understand tumour evolution and identify mechanisms of prostate cancer spread.
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Neoplasias de la Próstata , Masculino , Humanos , Filogenia , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Próstata/patología , Metástasis Linfática/patología , Vesículas Seminales/patologíaRESUMEN
OBJECTIVES: This three-arm randomized intervention study was carried out with the aim to evaluate the effects of a combined foot soak and lavender oil inhalation therapy on the severity of insomnia of patients with cancer. METHOD: This research was carried out in oncology and palliative services. Forty-five patients were randomly assigned to three groups. Throughout a 14-day period, 20 min of foot soak treatment was applied to the patients in the F group, patients in the L group were applied lavender oil inhalation therapy for 5 min and a combined treatment of foot soak and lavender oil inhalation therapy were applied to the patients in the FL group. Insomnia severity of the patients in all groups were evaluated twice using the Insomnia Severity Index at the baseline and on the fifteenth day. RESULTS: The severity of the insomnia of the patients in all groups was found to be moderate. The severity of the insomnia in the second evaluation was found to be statistically significantly lower in the L and FL groups (p<0.05) compared to the baseline evaluation within the group, however no significant difference was found in the F group (p>0.05). The effect size of a combined treatment of foot soak and lavender oil inhalation therapy on the severity of insomnia of patients in the FL group was higher and moderate (d = 0.684) compared to merely foot soak and merely lavender oil inhalation therapy. CONCLUSION: A combined treatment of foot soak and lavender oil inhalation therapy shall mitigate the severity of a moderate level of insomnia of patients with cancer.
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Aromaterapia , Lavandula , Neoplasias , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Trastornos del Inicio y del Mantenimiento del Sueño/etiología , Aceites de Plantas/uso terapéutico , Terapia Respiratoria , Neoplasias/complicacionesRESUMEN
When the COVID-19 pandemic broke out in the beginning of 2020, it became crucial to enhance early diagnosis with efficient means to reduce dangers and future spread of the viruses as soon as possible. Finding effective treatments and lowering mortality rates is now more important than ever. Scanning with a computer tomography (CT) scanner is a helpful method for detecting COVID-19 in this regard. The present paper, as such, is an attempt to contribute to this process by generating an open-source, CT-based image dataset. This dataset contains the CT scans of lung parenchyma regions of 180 COVID-19-positive and 86 COVID-19-negative patients taken at the Bursa Yuksek Ihtisas Training and Research Hospital. The experimental studies show that the modified EfficientNet-ap-nish method uses this dataset effectively for diagnostic purposes. Firstly, a smart segmentation mechanism based on the k-means algorithm is applied to this dataset as a preprocessing stage. Then, performance pretrained models are analyzed using different CNN architectures and with our Nish activation function. The statistical rates are obtained by the various EfficientNet models and the highest detection score is obtained with the EfficientNet-B4-ap-nish version, which provides a 97.93% accuracy rate and a 97.33% F1-score. The implications of the proposed method are immense both for present-day applications and future developments.
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Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disease with a prevalence of 1% over the age of 55. Neuropathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies that contain a variety of proteins and lipids including alpha-synuclein (α-syn). Although the formation of α-syn occurs intracellularly, it can also be found in the extracellular space where it can be taken up by neighboring cells. Toll-like receptor 2 (TLR2) is an immune system receptor that has been shown to recognize extracellular α-syn and modulate its uptake by other cells. Lymphocyte-activation gene 3 (LAG3), an immune checkpoint receptor, has also been proposed to play a role in extracellular α-syn internalization; however, a recent study has disputed this role. Internalized α-syn can trigger expression and secretion of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1ß, IL-2, and IL-6 and induce neuroinflammation, apoptosis, and mitophagy that results in cellular death. In this study, we tested if N-acetylcysteine (NAC), an anti-inflammatory and anti-carcinogenic drug, can circumvent the detrimental effects of neuroinflammation and induce an anti-inflammatory response by modulating transcription and expression of TLR2 and LAG3 receptors. Cells overexpressing wild-type α-syn were treated with TNF-α to induce inflammation followed by NAC to inhibit the deleterious effects of TNF-α-induced inflammation and apoptosis. SNCA gene transcription and α-syn protein expression were validated by q-PCR and Western blot (WB), respectively. Cell viability was measured, and apoptosis was evaluated by WB and terminal deoxynucleotidyl transferase nick end labeling methods. Alterations in LAG3 and TLR2 receptor levels were evaluated by immunofluorescent labeling, WB, and q-PCR. TNF-α not only increased inflammation but also increased endogenous and overexpressed α-syn levels. NAC treatment decreased expression of TLR2 and increased transcription of LAG3 receptor and diminished inflammation-mediated toxicity and cell death. Here, we demonstrate that NAC can reduce neuroinflammation that occurs as a result of alpha-synuclein overexpression, via a TLR2-associated pathway, making it a promising candidate for therapeutic intervention. Further studies are needed to elucidate molecular mechanisms and pathways related to neuroinflammation in PD and to develop possible new therapeutic approaches to slow the clinical progression of PD.
RESUMEN
In order to replenish iron stores and bring hemoglobin (Hb) levels back to normal, oral iron is the primary treatment option for women with iron deficiency anemia (IDA). This study investigated the efficacy and side effects of daily versus alternate-day, given single doses versus double doses oral iron supplementation for treating IDA. A retrospective cohort study was performed between 2021 and 2022, including 120 patients. Study group were divided into 4 age-sex-matched groups; Group I (nâ =â 30) and Group II (nâ =â 30) which were received ferrous sulphate tablets daily in single or double doses, respectively, containing 60 mg of elemental iron each. Groups III (nâ =â 30) and IV (nâ =â 30) were received a single and double dose on alternate days, respectively. The primary outcome was the mean difference in Hb from baseline at week 4. Gastrointestinal (GI) side effects were accepted as a secondary outcome. The daily single dose and alternate day double dose groups had median Hb changes of 2.3 (2.1) and 2.6 (1.8) g/dL. The differences in Hb between Groups I and II, I and III, and Groups IV and II, IV and III were significant (Pâ <â .001, Pâ =â .001, Pâ <â .001, and Pâ <â .001, respectively). There is no significant difference between groups regarding improving iron parameters such as serum iron, total iron binding capacity, transferrin saturation, and ferritin. The incidence of GI side effects were greater in double doses than in single doses of daily or alternate-day therapies (43.3% and 30% vs 10% and 3.3%). Daily or alternate-day double dose resulted in more side effects but less therapeutic efficacy in women with IDA. To find the best supplementation method, randomized controlled trials with a larger sample of participants, longer study lengths, and various iron doses may be helpful.
Asunto(s)
Anemia Ferropénica , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Femenino , Hierro , Anemia Ferropénica/etiología , Estudios Retrospectivos , Ferritinas , Administración Oral , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/complicaciones , Hemoglobinas/metabolismoRESUMEN
Decades of research have characterized diverse immune cells surveilling the CNS. More recently, the discovery of osseous channels (so-called 'skull channels') connecting the meninges with the skull and vertebral bone marrow has revealed a new layer of complexity in our understanding of neuroimmune interactions. Here we discuss our current understanding of skull and vertebral bone marrow anatomy, its contribution of leukocytes to the meninges, and its surveillance of the CNS. We explore the role of this hematopoietic output on CNS health, focusing on the supply of immune cells during health and disease.