Retraction of the Research Article: "Molecular targeting of FATP4 transporter for oral delivery of therapeutic peptide" by Z. Hu, S. Nizzero, S. Goel, L. E. Hinkle, X. Wu, C. Li, M. Ferrari and H. Shen.

[This retracts the article DOI: 10.1126/sciadv.aba0145.].

Molecular targeting of FATP4 transporter for oral delivery of therapeutic peptide.

Low oral bioavailability of peptide drugs has limited their application to parenteral administration, which suffers from poor patient compliance. Here, we show that molecular targeting of the FATP4 transporter is an effective approach to specifically transport long-chain fatty acid (LCFA)-conjugated peptides across the enterocytic membrane and, thus, enables oral delivery of drug peptides. We packaged LCFA-conjugated exendin-4 (LCFA-Ex4) into liposomes and coated with chitosan nanoparticles to form an orally deliverable Ex4 (OraEx4). OraEx4 protected LCFA-Ex4 from damage by the gastric fluid and released LCFA-Ex4 in the intestinal cavity, where LCFA-Ex4 was transported across the enterocyte membrane by the FAPT4 transporter. OraEx4 had a high bioavailability of 24.8% with respect to subcutaneous injection and exhibited a substantial hypoglycemic effect in murine models of diabetes mellitus. Thus, molecular targeting of the FATP4 transporter enhances oral absorption of therapeutic peptides and provides a platform for oral peptide drug development.

Investigation of parameters that determine Nano-DC vaccine transport.

Effective migration of dendritic cells into the lymphatic system organs is the prerequisite for a functional dendritic cell vaccine. We have previously developed a porous silicon microparticle (PSM)-based therapeutic dendritic cell vaccine (Nano-DC vaccine) where PSM serves both as the vehicle for antigen peptides and an adjuvant. Here, we analyzed parameters that determined dendritic cell uptake of PSM particles and Nano-DC vaccine accumulation in lymphatic tissues in a murine model of HER2-positive breast cancer. Our study revealed a positive correlation between sphericity of the PSM particles and their cellular uptake by circulating dendritic cells. In addition, the intravenously administered vaccines accumulated more in the spleens and inguinal lymph nodes, while the intradermally inoculated vaccines got enriched in the popliteal lymph nodes. Furthermore, mice with large tumors received more vaccines in the lymph nodes than those with small to medium size tumors. Information from this study will provide guidance on design and optimization of future therapeutic cancer vaccines.

Hashimoto's thyroiditis elicits decreased diagnostic efficacy of thyroid nodule ultrasound-guided fine needle aspiration.

BACKGROUND: False negative (FN) or false positive (FP) results of thyroid ultrasound-guided fine needle aspiration (US-guided FNA) cause missed diagnosis of thyroid cancer or unnecessary thyroidectomy. PURPOSE: To explore the impact of Hashimoto's thyroiditis (HT) on the diagnostic efficacy of US-guided FNA and to analyze the differences in diagnostic efficacy between US-guided FNA and thyroid ultrasonography (US) in patients with HT. METHOD: Medical records were reviewed retrospectively. Patients with and without Hashimoto's thyroiditis (HT) were included in the exposure and non-exposure group, respectively. RESULTS: HT was not an independent risk factor for thyroid cancer. The percentage of undetermined results of US-guided FNA (Bethesda I, III, IV) in the exposure group was significantly higher. The US-guided FNA's diagnostic sensitivity, specificity, and accuracy were significantly lower, and FP rate (FPR) and FN rate (FNR) were higher in the exposure group. In the exposure group, US tended to give higher diagnostic sensitivity, accuracy, PPV, NPV, and lower FPR and FNR. Receiver operating characteristic (ROC) curve analysis showed that, in the exposure group the diagnostic efficacy of thyroid US was significantly higher than of US-guided FNA. CONCLUSION: HT tends to cause undetermined results and elicit lower diagnostic performance of US-guided FNA. In patients with HT, the diagnostic efficacy of thyroid US is, at least, not inferior to US-guided FNA.

Activation of Rac by Asef2 promotes myosin II-dependent contractility to inhibit cell migration on type I collagen.

Non-muscle myosin II (MyoII) contractility is central to the regulation of numerous cellular processes, including migration. Rho is a well-characterized modulator of actomyosin contractility, but the function of other GTPases, such as Rac, in regulating contractility is currently not well understood. Here, we show that activation of Rac by the guanine nucleotide exchange factor Asef2 (also known as SPATA13) impairs migration on type I collagen through a MyoII-dependent mechanism that enhances contractility. Knockdown of endogenous Rac or treatment of cells with a Rac-specific inhibitor decreases the amount of active MyoII, as determined by serine 19 (S19) phosphorylation, and negates the Asef2-promoted increase in contractility. Moreover, treatment of cells with blebbistatin, which inhibits MyoII activity, abolishes the Asef2-mediated effect on migration. In addition, Asef2 slows the turnover of adhesions in protrusive regions of cells by promoting large mature adhesions, which has been linked to actomyosin contractility, with increased amounts of active ß1 integrin. Hence, our data reveal a new role for Rac activation, promoted by Asef2, in modulating actomyosin contractility, which is important for regulating cell migration and adhesion dynamics.