TH1902, a new docetaxel-peptide conjugate for the treatment of sortilin-positive triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a heterogeneous subgroup of cancers which lacks the expression and/or amplification of targetable biomarkers (ie, estrogen receptor, progestrogen receptor, and human epidermal growth factor receptor 2), and is often associated with the worse disease-specific outcomes than other breast cancer subtypes. Here, we report that high expression of the sortilin (SORT1) receptor correlates with the decreased survival in TNBC patients, and more importantly in those bearing lymph node metastases. By exploiting SORT1 function in ligand internalization, a new anticancer treatment strategy was designed to target SORT1-positive TNBC-derived cells both in vitro and in two in vivo tumor xenografts models. A peptide (TH19P01), which requires SORT1 for internalization and to which many anticancer drugs could be conjugated, was developed. In vitro, while the TH19P01 peptide itself did not exert any antiproliferative or apoptotic effects, the docetaxel-TH19P01 conjugate (TH1902) exerted potent antiproliferative and antimigratory activities when tested on TNBC-derived MDA-MB-231 cells. TH1902 triggered faster and more potent apoptotic cell death than did unconjugated docetaxel. The apoptotic and antimigratory effects of TH1902 were both reversed by two SORT1 ligands, neurotensin and progranulin, and on siRNA-mediated silencing of SORT1. TH1902 also altered microtubule polymerization and triggered the downregulation of the anti-apoptotic Bcl-xL biomarker. In vivo, both i.p. and i.v. administrations of TH1902 led to greater tumor regression in two MDA-MB-231 and HCC-70 murine xenograft models than did docetaxel, without inducing neutropenia. Altogether, the data demonstrates the high in vivo efficacy and safety of TH1902 against TNBC through a SORT1 receptor-mediated mechanism. This property allows for selective treatment of SORT1-positive TNBC and makes TH1902 a promising avenue for personalized therapy with the potential of improving the therapeutic window of cytotoxic anticancer drugs such as docetaxel.     

3D stereophotogrammetric image superimposition onto 3D CT scan images: the future of orthognathic surgery. A pilot study

The aim of this study was to register and assess the accuracy of the superimposition method of a 3-dimensional (3D) soft tissue stereophotogrammetric image (C3D image) and a 3D image of the underlying skeletal tissue acquired by 3D spiral computerized tomography (CT). The study was conducted on a model head, in which an intact human skull was embedded with an overlying latex mask that reproduced anatomic features of a human face. Ten artificial radiopaque landmarks were secured to the surface of the latex mask. A stereophotogrammetric image of the mask and a 3D spiral CT image of the model head were captured. The C3D image and the CT images were registered for superimposition by 3 different methods: Procrustes superimposition using artificial landmarks, Procrustes analysis using anatomic landmarks, and partial Procrustes analysis using anatomic landmarks and then registration completion by HICP (a modified Iterative Closest Point algorithm) using a specified region of both images. The results showed that Procrustes superimposition using the artificial landmarks produced an error of superimposition on the order of 10 mm. Procrustes analysis using anatomic landmarks produced an error in the order of 2 mm. Partial Procrustes analysis using anatomic landmarks followed by HICP produced a superimposition accuracy of between 1.25 and 1.5 mm. It was concluded that a stereophotogrammetric and a 3D spiral CT scan image can be superimposed with an accuracy of between 1.25 and 1.5 mm using partial Procrustes analysis based on anatomic landmarks and then registration completion by HICP.     

Enzymatic markers of salivary cell injury in saliva of type 1 diabetic children

To find evidence of salivary gland involvement in human type I diabetes, we explored the changes in aminotransferase and lactate dehydrogenase activities, as indices of cellular injury, in the whole saliva of diabetic children. Although no significant difference in these enzymatic activities was observed between control and diabetic children as a whole, a negative correlation was found between enzymatic activities and duration of the disease, the highest values being detected in the diabetic subgroup diagnosed for less than 4 years. This suggests that some cell damage could be present in salivary glands of recently diagnosed diabetic children, likely as a result of immune-mediated alterations. In conclusion, these results may support the hypothesis that, as in rodents, the salivary glands could be an additional target of the immunological attack mainly directed against pancreatic beta-cells and resulting in type 1 diabetes.     

Recombinant tissue plasminogen activator enhances microglial cell recruitment after stroke in mice

The effect of recombinant human tissue plasminogen activator (rtPA) on neuroinflammation after stroke remains largely unknown. Here, we tested the effect of rtPA on expression of cellular adhesion molecules, chemokines, and cytokines, and compared those with levels of inflammatory cell recruitment, brain injury, and mortality over 3 days after transient middle cerebral artery occlusion (MCAO) in mice. Mortality was dramatically increased after rtPA treatment compared with saline treatment during the first day of reperfusion. Among the animals that survived, rtPA significantly increased CCL3 expression, microglia recruitment, and cerebral infarction 6 hours after MCAO. In contrast, the extent of neutrophils and macrophages infiltration in the brain was similar in both saline- and rtPA-treated animals. Recombinant human tissue plasminogen activator induced Il1b and Tnf expression, 6 and 72 hours after MCAO, respectively, and dramatically reduced interleukin 6 (IL-6) level 24 hours after reperfusion. A dose response study confirmed the effect of rtPA on CCL3 and Il1b expressions. The effect was similar at the doses of 1 and 10 mg/kg. In conclusion, we report for the first time that rtPA amplified microglia recruitment early after stroke in association with a rapid CCL3 production. This early response may take part in the higher susceptibility of rtPA-treated animals to reperfusion injury.     

Are the antiplatelet and profibrinolytic properties of selective serotonin-reuptake inhibitors relevant to their brain effects?

The serotonin transporter (SERT) is found in neuron and platelet membranes. Selective serotonin-reuptake inhibitors (SSRIs) are widely prescribed for severe depression. They may at least partly counteract the effects of serotonin on the vascular biology system, can lower agonists-induced platelet activation, aggregation and procoagulant activity in vitro, thus modulating platelet thrombogenicity. Other effects, such as those mediated through PAI-1 modulation, may indirectly influence neurobiology-relevant mechanisms involved in depression. Patients receiving SSRIs are at increased bleeding risk and decreased risk of arterial occlusive events, such as myocardial infarction, compared to those using non-SSRI antidepressants. The objectives of this review were to highlight antiplatelet and profibrinolytic properties of SSRIs and discuss the potential role of these activities in the context of SSRI brain effects.     

Role of Preoperative Basal Calcitonin Levels in the Timing of Prophylactic Thyroidectomy in Patients With Germline RET Mutations

Background

The American Thyroid Association (ATA) published recommendations for the timing of prophylactic surgery for medullary thyroid carcinoma based on the specific mutation, patient age, family history, and serum calcitonin levels. The aim of this study was to assess the role of preoperative basal calcitonin (prebCt) levels in predicting the presence of medullary carcinoma of the thyroid in patients with RET mutations.

Methods

We conducted a retrospective study in two endocrine surgery departments. Between 1986 and 2012, a total of 32 patients with RET mutations underwent prophylactic thyroidectomy. The patients were stratified into four ATA risk levels: A, B, C, and D.

Results

All of the patients were biologically cured. Microcarcinoma was observed in the final pathology report for four of the 20 patients with normal prebCt (25 %) and for nine of the 12 patients with elevated prebCt (75 %). In the level A group, four patients with normal prebCt and one patient with elevated prebCt presented with microcarcinoma. In the level C group, one patient with normal prebCt and six of the seven patients with elevated prebCt (86 %) presented with microcarcinoma.

Conclusions

PrebCt can predict the presence of microcarcinoma according to surgical pathological analysis. Patients with microcarcinoma can be biochemically and clinically cured using prophylactic thyroidectomy.