ABSTRACT
The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA-directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas.
Subject(s)
Mitosis , Protein Inhibitors of Activated STAT , Humans , Protein Inhibitors of Activated STAT/metabolism , Protein Inhibitors of Activated STAT/genetics , Animals , Cell Line, Tumor , Mice , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology , Thyroid Neoplasms/metabolism , RNA Interference , Spindle Apparatus/metabolism , Molecular Chaperones/metabolism , Molecular Chaperones/genetics , Xenograft Model Antitumor Assays , Proteasome Endopeptidase Complex/metabolism , Sumoylation , Carcinoma/genetics , Carcinoma/metabolism , Carcinoma/pathology , FemaleABSTRACT
Severe hypokalaemia causing rhabdomyolysis (RML) in primary aldosteronism (PA) is a rare entity, and only a few cases have been reported over the last four decades. This systematic review and case report aims to gather all published data regarding a hypokalaemic RML as presentation of PA in order to contribute to the early diagnosis of this extremely rare presentation. With the use of PubMed Central, EMBASE, and Google Scholar, a thorough internet-based search of the literature was conducted to identify articles and cases with RML secondary to hypokalaemia due to PA between June 1976 and July 2023. The case study concerns a 68-year-old male patient with hypokalaemic RML at presentation of PA. In the systematic review of the literature, 37 cases of RML secondary to hypokalaemia due to PA have been reported to date. In summary, the median age was 47.5 years, the male/female ratio was 17/21, all patients presented symptoms (weakness and/or myalgia), all the patients were hypertensive, and only four patients had complications with acute kidney injury (AKI). Although PA rarely presents with RML, it should be suspected when marked hypokalaemia and hypertension are also present. Early detection and management are essential to reduce the frequency of manifestations such as AKI.
Subject(s)
Acute Kidney Injury , Hyperaldosteronism , Hypertension , Hypokalemia , Rhabdomyolysis , Humans , Male , Female , Middle Aged , Aged , Hypokalemia/complications , Hypokalemia/diagnosis , Hypertension/complications , Hypertension/diagnosis , Rhabdomyolysis/complications , Rhabdomyolysis/diagnosis , Acute Kidney Injury/etiology , Hyperaldosteronism/complications , Hyperaldosteronism/diagnosisABSTRACT
A 47-year-old man was attended at the emergency room for severe chest pain after eating sausage with subsequent vomiting and mild upper gastrointestinal bleeding. In the chest radiography we could not see abnormalities. He referred previous episodes of choking without consulting. The urgent gastroscopy detected tertiary contractile activity (nutcracker esophagus) and a foreign body in the lower third of the esophagus. After removing the food bolus, we observed a 4 cm longitudinal tear compatible with esophageal rupture or Boerhaave's syndrome in the right posterior wall of the lower esophagus, proximal to the gastroesophageal junction. Thoracic-abdominal computed tomography (TC) confirmed a perforation of the lower esophagus, with pneumothorax and cervical and chest emphysema. Surgical treatment was indicated: esophageal suture, myotomy and gastric fundoplication. The patient presented good evolution. Boerhaave's syndrome is a rare syndrome, but with high mortality (35%). Mackler triad is very characteristic: vomiting, retrosternal pain and cervical subcutaneous emphysema; but it occurs rarely. Chest radiography is useful, showing abnormalities in up to 90% of patients. The differential diagnosis includes cardiorespiratory disorders: acute myocardial infarction, spontaneous pneumothorax, pericarditis or pneumonia. The role of endoscopy is small, mainly limited to prosthesis placement in high-risk surgical patients. In our case the chest radiograph was initially normal, probably related to bolus impaction and, in presence of upper gastrointestinal bleeding, gastroscopy was performed which allowed us to early diagnosis and treatment.
Subject(s)
Esophageal Perforation/diagnostic imaging , Gastroscopy/methods , Mediastinal Diseases/diagnostic imaging , Foreign Bodies/complications , Foreign Bodies/therapy , Humans , Male , Middle Aged , Tomography, X-Ray ComputedABSTRACT
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