Citations

Aptamers are short DNA or RNA sequences that adopt 3D structures and can bind to protein targets with high binding affinity and specificity. Aptamers exhibit excellent tissue penetration, are inexpensive to produce, and can be internalized by cells. Therefore, aptamers are attractive targeting ligands to direct the delivery of theranostic agents to the desired cells. Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen that is aberrantly overexpressed on many epithelial-derived cancers, including on cholangiocarcinoma (CCA) cells. Its expression on treatment-resistant cancer stem cells, along with its abundance in the CCA tumor microenvironment, highlights the need to develop EpCAM-targeted therapies for CCA. Herein, an in silico approach was used to design and screen DNA aptamers capable of binding to the EpCAM monomer and homodimer. Two aptamers, PLD01 and PLD02, met the selection criteria and were validated in vitro. Both aptamers exhibited high affinity for EpCAM+ CCA cells, with negligible binding to EpCAM- leukemia cells. Modified versions of PLD01 and PLD02 were successfully incorporated into the membranes of milk-derived nanovesicles. PLD01-functionalized nanovesicles enabled EpCAM-targeted delivery of the therapeutic cargo to CCA cells. In summary, these EpCAM-targeting aptamers can be utilized to direct the delivery of theranostic agents to EpCAM-expressing cells.

Hurler–Scheie syndrome (MPS IH/S), also known as mucopolysaccharidosis type I-H/S (MPS IH/S), is a lysosomal storage disorder caused by deficiency of the enzyme alpha-L-iduronidase (IDUA) leading to the accumulation of glycosaminoglycans (GAGs) in various tissues, resulting in a wide range of symptoms affecting different organ systems. Postgenomic omics technologies offer the promise to understand the changes in proteome, phosphoproteome, and phosphorylation-based signaling in MPS IH/S. Accordingly, we report here a large dataset and the proteomic and phosphoproteomic analyses of fibroblasts derived from patients with MPS IH/S ( n = 8) and healthy individuals ( n = 8). We found that protein levels of key lysosomal enzymes such as cathepsin D, prosaposin, arylsulfatases (arylsulfatase A and arylsulfatase B), and IDUA were downregulated. We identified 16,693 unique phosphopeptides, corresponding to 4,605 proteins, in patients with MPS IH/S. We found that proteins related to the cell cycle, mitotic spindle assembly, apoptosis, and cytoskeletal organization were differentially phosphorylated in MPS IH/S. We identified 12 kinases that were differentially phosphorylated, including hyperphosphorylation of cyclin-dependent kinases 1 and 2, hypophosphorylation of myosin light chain kinase, and calcium/calmodulin-dependent protein kinases. Taken together, the findings of the present study indicate significant alterations in proteins involved in cytoskeletal changes, cellular dysfunction, and apoptosis. These new observations significantly contribute to the current understanding of the pathophysiology of MPS IH/S specifically, and the molecular mechanisms involved in the storage of GAGs in MPS more generally. Further translational clinical omics studies are called for to pave the way for diagnostics and therapeutics innovation for patients with MPS IH/S.

AbstractBackgroundPrimary cutaneous γδ T‐cell lymphoma (CGD‐CTL) is a rare malignancy that classically exhibits an aggressive clinical phenotype.ObjectivesReview cases of mycosis fungoides with a γδ phenotype that demonstrated an indolent clinical course.MethodsRetrospective review of patients diagnosed with MF with a γδ phenotype and an indolent clinical course between 2018 and 2022 treated at the University of Utah.ResultsFive patients ages 4‐81 years old were identified. All presented with clinically persistent patch or plaque‐stage disease, and histopathology showed primarily epidermotropic infiltrates positive for TCR delta via immunostaining. None of these patients have required aggressive treatment with multiagent chemotherapy.ConclusionsThere exists a subset of indolent CGD‐TCL patients who are clinicopathologically distinct from classic CGD‐CTL and clinically resembling indolent MF. Therefore, we prefer the term “MF with γδ phenotype” for these rare cases.

AbstractObjectiveTo evaluate the clinical efficacy of vidian neurectomy (VN) or posterior nasal neurectomy (PNN) combined with endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP).Data SourcesA systematic search of six databases (PubMed, SCOPUS, Embase, Web of Science, Google Scholar, and Cochrane) was conducted to identify relevant studies up to May 2024.Review MethodsThe effects of combining VN or PNN with ESS were evaluated in comparison to ESS alone. Outcomes were assessed by evaluating changes in Lund‐Kennedy score, patient‐reported symptom scores (VAS), quality of life, as well as adverse effects and recurrence rate of CRSwNP.ResultsA total of 6 studies, comprising 407 patients, were included in the analysis. The neurectomy group showed significant improvements in Lund‐Kennedy score (SMD = 0.7276 [0.5695; 0.8857]), with statistically significant improvements maintained at 6, 12, and 24 months postoperatively. The treatment group maintained better improvements in sinusitis‐related quality of life (SMD = 0.4540 [0.1784; 0.7297]) and VAS (SMD = 0.7096 [0.4356; 0.9837]) until 12 months postoperatively, but not at 24 months. Regarding adverse effects, additional neurectomy did not significantly induce epistaxis (odds ratio [OR] = 0.9806 [0.2348; 4.0960]) or dry eye (OR = 2.4194 [0.1114; 52.5255]) compared to the control group. On the other hand, there was no difference in the recurrence rate of CRSwNP between the 2 groups during the follow‐up periods.ConclusionAdditional neurectomy shows better efficacy in improving endoscopic findings and symptoms in patients with CRSwNP and appears to be a safe and effective treatment.