Prognostic value of serum progranulin in de novo adult acute myeloid leukemia patients

Abstract Background Elevated serum progranulin (PGRN) levels have been associated with a wide range of different human malignancies. However, data available on the role of PGRN in hematological malignancies are limited. Methods Measurement of the PGRN level in serum of adult de novo acute myeloid leukemia (AML) patients using enzyme-linked immunosorbent assay (ELISA) was performed. Results The mean serum PGRN level in AML patients was higher than that in controls (346.08 pg/ml ± 64.46 vs 155 pg/ml ± 63 respectively; p= 0.001). After a mean duration of follow-up equaling 140 days, patients with high serum PGRN (i.e., higher than 370.5 pg/ml) had inferior overall survival (OS) in comparison to patients with low serum PGRN (i.e., lower than 370.5 pg/ml) (OS = 25% vs 60.7%, mean survival = 107 days vs 256.5 days, p= 0.007). On the other hand, remitted patients on day 28 with high serum PGRN (i.e., higher than 307.5 pg/ml) did not differ from those with low serum PGRN (i.e., lower than 307.5 pg/ml) regarding disease-free survival (DFS) (DFS = 78.6% vs. 87.5%, mean survival = 301.3 days vs. 283.5 days, p= 0.789). Moreover, the serum PGRN level was associated with inferior OS (p= 0.024) on multivariate analysis. Conclusion Adult de novo AML patients have elevated serum PGRN levels and a high PGRN level is associated with an inferior OS.

Progranulin concentration in relation to bone mineral density among obese individuals

ABSTRACT Objective Adipose tissue, particularly visceral adipose tissue, secretes a variety of cytokines, among which progranulin is a glycoprotein related to the immune system. Along with other secreted proteins, progranulin may be associated with bone mineral density. The aim of this study was to find out whether there are associations between the progranulin and bone mineral density among obese people. Subjects and methods This cross-sectional study was conducted on 244 obese participants (aged 22-52). Serum progranulin, high sensitive C-reactive protein, oxidised-low dencity lipoprotein, tumor necrosis factor-α, parathormone, vitamin D, and interleukins of 1 β, 4, 6, 10, 13, and 17 concentrations were measured. Anthropometric measurements, body composition and bone mineral density were also assessed. Results Serum progranulin was directly associated with interleukin-6 and interleukin-1β, while it had a negative association with interleukin-17 and tumor necrosis factor-α. We also observed a statistically significant direct association between progranulin concentration and visceral fat, abdominal fat, waist, abdominal and hip circumferences, hip T-score, and Z-score and T-score for the lumbar region. A partial correlation test has also shown a significant positive correlation regarding serum progranulin and the hip Z-score. Moreover, progranulin level is inversely associated with ospteopenia (P = 0.04 and CI: 0.17,0.96). Conclusion Our study revealed that central obesity may be related to increased progranulin concentration. In addition, progranulin concentration was directly related to bone formation parameters, which indicates the protective effects of progranulin on bone density. Further studies are needed to clarify the exact mechanisms underlying these associations.

New discovery rarely runs smooth: an update on progranulin/TNFR interactions

Progranulin (PGRN) is a growth factor implicated in various pathophysiological processes, including wound healing, inflammation, tumorigenesis, and neurodegeneration. It was previously reported that PGRN binds to tumor necrosis factor receptors (TNFR) and has therapeutic effects in inflammatory arthritis (Tang et. al, in Science 332:478-484, 2011); however, Chen et al. reported their inability to demonstrate the PGRN-TNFR interactions under their own conditions (Chen et. al, in J Neurosci 33:9202-9213, 2013). A letter-to-editor was then published by the original group in response to the Chen et al. paper that discussed the reasons for the latter's inability to recapitulate the interactions. In addition, the group published follow-up studies that further reinforced and dissected the interactions of PGRN-TNFR. Recently, the dispute about the legitimacy of PGRN-TNFR interactions appears to be finally settled with independent confirmations of these interactions in various conditions by numerous laboratories. This review presents a chronological update on the story of PGRN-TNFR interactions, highlighting the independent confirmations of these interactions in various diseases and conditions.

Primary progressive aphasia: a dementia of the language network / Afasia progressiva primária: uma demência da rede de linguagem

Primary progressive aphasia (PPA) is a clinical syndrome diagnosed when three core criteria are met. First, there should be a language impairment (i.e., aphasia) that interferes with the usage or comprehension of words. Second, the neurological work-up should determine that the disease is neurodegenerative, and therefore progressive. Third, the aphasia should arise in relative isolation, without equivalent deficits of comportment or episodic memory. The language impairment can be fluent or non-fluent and may or may not interfere with word comprehension. Memory for recent events is preserved although memory scores obtained in verbally mediated tests may be abnormal. Minor changes in personality and behavior may be present but are not the leading factors that bring the patient to medical attention or that limit daily living activities. This distinctive clinical pattern is most conspicuous in the initial stages of the disease, and reflects a relatively selective atrophy of the language network, usually located in the left hemisphere. There are different clinical variants of PPA, each with a characteristic pattern of atrophy. The underlying neuropathological diseases are heterogeneous and can include Alzheimer's disease as well as frontotemporal lobar degeneration. The clinician's task is to recognize PPA and differentiate it from other neurodegenerative phenotypes, use biomarkers to surmise the nature of the underlying neuropathology, and institute the most fitting multimodal interventions.

A afasia progressiva primária (APP) é uma síndrome clínica diagnosticada quando três critérios centrais são preenchidos. Inicialmente deve haver comprometimento da linguagem (afasia) que interfere com o uso ou a compreensão das palavras. Em segundo lugar, os métodos diagnósticos devem determinar que a doença é neurodegenerativa e, portanto, progressiva. Por último, a afasia deve emergir de forma relativamente isolada, sem alterações equivalentes de comportamento ou memória episódica. O comprometimento da linguagem pode ser de tipo fluente ou não fluente, e pode ou não interferir com a compreensão de palavras. A memória para eventos recentes está preservada, embora escores de memória em testes verbais possam ser anormais. Alterações discretas de personalidade e comportamento podem estar presentes, mas não são os fatores que levam o paciente ao atendimento médico ou que o limitam em suas atividades de vida diária. Este padrão distinto é mais evidente nas fases iniciais da doença e reflete a atrofia relativamente seletiva da rede de linguagem, geralmente localizada no hemisfério cerebral esquerdo. Há diferentes variantes clínicas da APP, cada uma com padrão de atrofia característico. Os substratos neuropatológicos são heterogêneos e podem incluir a doença de Alzheimer e a degeneração lobar frontotemporal. A tarefa do clínico é reconhecer a APP e diferenciá-la de outros fenótipos neurodegenerativos, utilizar biomarcadores para inferir a natureza da neuropatologia subjacente e instituir as intervenções multimodais cabíveis.

Progranulin promotes neurite outgrowth and neuronal differentiation by regulating GSK-3β

Progranulin (PGRN) has recently emerged as a key player in a subset of frontotemporal dementias (FTD). Numerous mutations in the progranulin gene have been identified in patients with familial or sporadic frontotemporal lobar degeneration (FTLD). In order to understand the molecular mechanisms by which PGRN deficiency leads to FTLD, we examined activity of PGRN in mouse cortical and hippocampal neurons and in human neuroblastoma SH-SY5Y cells. Treatment of mouse neurons with PGRN protein resulted in an increase in neurite outgrowth, supporting the role of PGRN as a neurotrophic factor. PGRN treatment stimulated phosphorylation of glycogen synthase kinase-3 beta (GSK-3β) in cultured neurons. Knockdown of PGRN in SH-SY5Y cells impaired retinoic acid induced differentiation and reduced the level of phosphorylated GSK-3β. PGRN knockdown cells were also more sensitized to staurosporine-induced apoptosis. These results reveal an important role of PGRN in neurite outgrowth and involvement of GSK-3β in mediating PGRN activity. Identification of GSK-3β activation as a downstream event for PGRN signaling provides a mechanistic explanation for PGRN activity in the nervous system. Our work also suggest that loss of axonal growth stimulation during neural injury repair or deficits in axonal repair may contribute to neuronal damage or axonal loss in FTLD associated with PGRN mutations. Finally, our study suggests that modulating GSK-3β or similar signaling events may provide therapeutic benefits for FTLD cases associated with PGRN mutations.