Clinical predictors of I-131 therapy failure in differentiated thyroid cancer by machine learning: A single-center experience.

Well-differentiated thyroid carcinoma is predominantly a slow-growing malignancy, amendable to treatment, and has an excellent prognosis following thyroidectomy and radioiodine (RAI) therapy. However, patients who fail the initial RAI treatment attempt may require repeated RAI or other treatments and with this, comes an associated impact on patient quality of life. Therefore, the anticipation of patients in whom there is a higher risk of RAI failure may help in patient risk stratification and subsequent management. We conducted a retrospective review to determine the factors associated with initial RAI therapy failure in well-differentiated thyroid cancer patients. Using scikit-learn from Python, we implemented a machine-learning algorithm to determine the clinical patient factors associated with a higher likelihood of treatment resistance. We found that clinical factors such as tumor focality (P = 0.026) and lymph node invasion at surgical resection (P = 0.0135) were significantly associated with initial treatment failure following RAI. Elevated serum thyroglobulin (Tg) and Tg antibody levels following surgery but before RAI were also associated with treatment resistance (P < 0.0001 and P = 0.011 respectively). Less expected factors such as decreased time from surgery to RAI were also associated with treatment failure, however not to a statistically significant degree (P > 0.064). Clinical outcomes following RAI can be stratified by identifying factors that are associated with initial treatment failure. These findings can help restratify patients for RAI treatment and change patient management in certain cases. Such stratification will ultimately help to optimize successful treatment outcomes and improve patient quality of life.

Prostate Cancer Pulmonary Metastasis Presenting as a Ground-Glass Pulmonary Nodule on 68Ga-PSMA-11 PET/CT.

Ga-prostate-specific membrane antigen 11 (PSMA) PET/CT imaging accurately depicts metastatic prostate adenocarcinoma (PCa). Pulmonary metastases of PCa are often overlooked on follow-up imaging in patients after initial treatment and following androgen deprivation therapy. Here we present a rare case of biopsy-proven PCa pulmonary metastasis with a ground-glass appearance. The increased PSMA expression and the evolving CT features of the solid component of the ground-glass nodule detected by PSMA PET/CT imaging led to surgical resection and PET/CT-guided therapy.

Folding of tetrameric p53: oligomerization and tumorigenic mutations induce misfolding and loss of function.

The physiologically active form of p53 consists of a tetramer of four identical 393-amino-acid subunits associated via their tetramerization domains (TDs; residues 325-355). One in two human tumors contains a point mutation in the DNA binding domain (DBD) of p53 (residues 94-312). Most existing studies on the effects of these mutations on p53 structure and function have been carried out on the isolated DBD fragment, which is monomeric. Recent structural evidence, however, suggests that DBDs may interact with each other in full-length tetrameric forms of p53. Here, we investigate the effects of tumorigenic DBD mutations on the folding of p53 in its tetrameric form. We employ the construct consisting of DBD and TD (amino acids 94-360). We characterize the stability and conformational state of the tumorigenic DBD mutants R248Q, R249S, and R282Q using equilibrium denaturation and functional assays. Destabilizing mutations cause DBD to misfold when it is part of the p53 tetramer, but not when it is monomeric. This conformation is populated under moderately destabilizing conditions (10 degrees C in 2 M urea, and at physiological temperature in the absence of denaturant). Under those same conditions, it is not present in the isolated DBD fragment or in the presence of the TD mutation L344P, which abolishes tetramerization. Misfolding appears to involve intramolecular DBD-DBD association within a single tetrameric molecule. This association is promoted by destabilization of DBD (caused by mutation or elevated temperature) and by the high local DBD concentration enforced by tetramerization of TD. Disrupting the nonnative DBD-DBD interaction or transiently inhibiting tetramerization and allowing p53 to fold as a monomer may be potential strategies for pharmacological intervention in cancer.

Effect of interdomain linker length on an antagonistic folding-unfolding equilibrium between two protein domains.

Fusion of one protein domain with another is a common event in both evolution and protein engineering experiments. When insertion is at an internal site (e.g., a surface loop or turn), as opposed to one of the termini, conformational strain can be introduced into both domains. Strain is manifested by an antagonistic folding-unfolding equilibrium between the two domains, which we previously showed can be parameterized by a coupling free-energy term (DeltaG(X)). The extent of strain is predicted to depend primarily on the ratio of the N-to-C distance of the guest protein to the distance between ends of the surface loop in the host protein. Here, we test that hypothesis by inserting ubiquitin (Ub) into the bacterial ribonuclease barnase (Bn), using peptide linkers from zero to 10 amino acids each. DeltaG(X) values are determined by measuring the extent to which Co(2+) binding to an engineered site on the Ub domain destabilizes the Bn domain. All-atom, unforced Langevin dynamics simulations are employed to gain structural insight into the mechanism of mechanically induced unfolding. Experimental and computational results find that the two domains are structurally and energetically uncoupled when linkers are long and that DeltaG(X) increases with decreasing linker length. When the linkers are fewer than two amino acids, strain is so great that one domain unfolds the other. However, the protein is able to refold as dimers and higher-order oligomers. The likely mechanism is a three-dimensional domain swap of the Bn domain, which relieves conformational strain. The simulations suggest that an effective route to mechanical unfolding begins with disruption of the hydrophobic core of Bn near the Ub insertion site.