Titin is the largest known protein and a critical determinant of myofibril elasticity and sarcomere structure in striated muscle. Accumulating evidence that mRNA transcripts are post-transcriptionally regulated by specific motifs located in the flanking untranslated regions (UTRs) led us to consider the role of titin 5′-UTR in regulating its translational efficiency. Titin 5′-UTR is highly homologues between human, mouse, and rat, and sequence analysis revealed the presence of a stem-loop and two upstream AUG codons (uAUGs) converging on a shared in frame stop codon. We generated a mouse titin 5′-UTR luciferase reporter construct and targeted the stem-loop and each uAUG for mutation. The wild-type and mutated constructs were transfected into the cardiac HL-1 cell line and primary neonatal rat ventricular myocytes (NRVM). SV40 driven 5′-UTR luciferase activity was significantly suppressed by wild-type titin 5′-UTR (~70% in HL-1 cells and ~60% in NRVM). Mutating both uAUGs was found to alleviate titin 5′-UTR suppression, while eliminating the stem-loop had no effect. Treatment with various growth stimuli: pacing, PMA or neuregulin had no effect on titin 5′-UTR luciferase activity. Doxorubicin stress stimuli reduced titin 5′-UTR suppression, while H2O2 had no effect. A reported single nucleotide polymorphism (SNP) rs13422986 at position −4 of the uAUG2 was introduced and found to further repress titin 5′-UTR luciferase activity. We conclude that the uAUG motifs in titin 5′-UTR serve as translational repressors in the control of titin gene expression, and that mutations/SNPs of the uAUGs or doxorubicin stress could alter titin translational efficiency.

Ventricular pseudoaneurysm is an uncommon, potentially fatal complication that has been associated with myocardial infarction, cardiac surgery, chest trauma, and infectious processes. Diagnosis can be challenging, as cases are rare and slowly progressing and typically lack identifiable features on clinical presentation. As a result, advanced imaging techniques have become the hallmark of identification. Ahead, we describe a patient who presents with acute decompensated heart failure and was incidentally discovered to have a large right ventricular pseudoaneurysm that developed following previous traumatic anterior rib fracture.

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The authors reviewed retrospective cases of 2 women - one aged 78 years and the other aged 86 years - with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer treated with combination palbociclib/letrozole who presented with hyperuricemia. In both cases, the patients experienced hyperuricemia and neutropenia that required palbociclib to be temporarily discontinued and its dose to be subsequently reduced. Although study data have demonstrated that combination palbociclib/letrozole is safe and effective as a first-line treatment option for patients with advanced ER-positive, HER2-negative breast cancer, the efficacy and safety of cyclin-dependent kinase inhibitors, including their adverse events, still remains an active area of research. The authors postulate that hyperuricemia may be a potential adverse event of palbociclib not yet reported in randomized control studies or in clinical practice.

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