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Silvia Sookoian,Carlos J. Pirola 대한간학회 2020 Clinical and Molecular Hepatology(대한간학회지) Vol.26 No.4
Despite more than two decades of extensive research focusing on nonalcoholic fatty liver disease (NAFLD), no approved therapy for steatohepatitis—the severe histological form of the disease—presently exists. More importantly, new drugs and small molecules with diverse molecular targets on the pathways of hepatocyte injury, inflammation, and fibrosis cannot achieve the primary efficacy endpoints. Precision medicine can potentially overcome this issue, as it is founded on extensive knowledge of the druggable genome/proteome. Hence, this review summarizes significant trends and developments in precision medicine with a particular focus on new potential therapeutic discoveries modeled via systems biology approaches. In addition, we computed and simulated the potential utility of the NAFLD polygenic risk score, which could be conceptually very advantageous not only for early disease detection but also for implementing actionable measures. Incomplete knowledge of the druggable NAFLD genome severely impedes the drug discovery process and limits the likelihood of identifying robust and safe drug candidates. Thus, we close this article with some insights into emerging disciplines, such as chemical genetics, that may accelerate accurate identification of the druggable NAFLD genome/proteome.
Silvia Sookoian,Carlos J. Pirola 대한간학회 2023 Clinical and Molecular Hepatology(대한간학회지) Vol.29 No.-
The knowledge on the genetic component of non-alcoholic fatty liver disease (NAFLD) has grown exponentially over the last 10 to 15 years. This review summarizes the current evidence and the latest developments in the genetics of NAFLD and non-alcoholic steatohepatitis (NASH) from the immune system’s perspective. Activation of innate and or adaptive immune response is an essential driver of NAFLD disease severity and progression. Lipid and immune pathways are crucial in the pathophysiology of NAFLD and NASH. Here, we highlight novel applications of genomic techniques, including single-cell sequencing and the genetics of gene expression, to elucidate the potential involvement of NAFLD/NASH-risk alleles in modulating immune system cells. Together, our focus is to provide an overview of the potential involvement of the NAFLD/NASH-related risk variants in mediating the immune-driven liver disease severity and diverse systemic pleiotropic effects.
Carlo Giulioni,Giacomo Maria Pirola,Martina Maggi,Lucia Pitoni,Demetra Fuligni,Mattia Beltrami,Vanessa Palantrani,Virgilio De Stefano,Valentina Maurizi,Daniele Castellani,Andrea Benedetto Galosi 대한배뇨장애요실금학회 2024 International Neurourology Journal Vol.28 No.1
To assess the effectiveness and safety of various techniques of pudendal nerve neurolysis (PNN) in patients with pudendal nerve entrapment (PNE). A comprehensive literature search was conducted on May 20th, 2023, using Scopus, PubMed, and Embase databases. Only studies in English involving adults were accepted, while meeting abstracts and preclinical studies were excluded. A total of 34 papers were included. Transperineal PNN emerged as a promising technique, demonstrating significant potential in alleviating pain, restoring erectile function in males, and improving the resolution of urinary stress incontinence in females. Furthermore, the bilateral approach consistently yielded positive outcomes in addressing urinary symptoms. The transgluteal technique appeared particularly suitable for cases of posterior PNE, situated between the sacrospinous ligament and the lesser sciatic foramen. A progressive amelioration of painful symptoms was observed during follow-up. Minimally invasive PNN is evolving and enables decompression along the entire proximal tract up to the Alcock canal, minimizing the risk of comorbidities. In addition to reducing pudendal neuralgia, robot-assisted and laparoscopic approaches determined a reduction in lower urinary tract symptoms and an improvement in erectile function, though further studies are required to corroborate these findings. PNN emerges as an effective treatment for PNE with minimal morbidity. Therefore, PNN should be tailored according to the site of PNE to enhance functional outcomes and improve patient quality of life.
Recurrent <i>ETNK1</i> mutations in atypical chronic myeloid leukemia
Gambacorti-Passerini, Carlo B.,Donadoni, Carla,Parmiani, Andrea,Pirola, Alessandra,Redaelli, Sara,Signore, Giovanni,Piazza, Vincenzo,Malcovati, Luca,Fontana, Diletta,Spinelli, Roberta,Magistroni, Vera American Society of Hematology 2015 Blood Vol.125 No.3
<P>Despite the recent identification of recurrent <I>SETBP1</I> mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the <I>ETNK1</I> gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of <I>ETNK1</I> variants in 6 (8.8%) of 68 aCML and 2 (2.6%) of 77 chronic myelomonocytic leukemia samples. These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S). They were all heterozygous and present in the dominant clone. The intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples (<I>P</I> < .05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 wild type, ETNK1-N244S, and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76 ± 0.07) and ETNK1-H243Y (0.37 ± 0.02) than in ETNK1-WT (1.37 ± 0.32; <I>P</I> = .01 and <I>P</I> = .0008, respectively), suggesting that <I>ETNK1</I> mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic <I>ETNK1</I> mutations in the context of myeloproliferative/myelodysplastic disorders.</P>