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BACKGROUND Some, but not all, patients with primary hyperparathyroidism (PHPT) and kidney stone disease (KSD) are cured of their nephrolithiasis after parathyroidectomy. The goal of this study is to identify risk factors for recurrent KSD despite successful parathyroidectomy in known stone formers with PHPT. METHODS We conducted a single-center retrospective review of patients presenting to Urology clinic with KSD between 1/2008 and 7/2018, who were diagnosed with concurrent PHPT, and underwent definitive parathyroidectomy. Laboratory testing for serum calcium, PTH, phosphorus and 25-OH-vitamin D, and 24-hour urine studies for volume, pH, calcium, citrate, oxalate, uric acid, sodium, and creatinine was performed pre- and post-parathyroidectomy. Stone recurrence was determined on routine diagnostic imaging or by symptomatic KSD. RESULTS Mean age at parathyroidectomy was 57±14years. Pre-parathyroidectomy, mean serum calcium, 24-hour urine calcium, and PTH were 10.6±0.5 mg/dL, 378±209 mg/day, and 114±97 pg/mL, respectively. 26/69 (38%) had multi-gland parathyroid disease. After parathyroidectomy, serum calcium and PTH levels normalized in 69/69 and 62/69 patients, respectively. However, 37/69 (54%) patients had persistent hypercalciuria post-operatively. 16/69 (23%) had recurrent KSD on average 2.0±1.6 years after parathyroidectomy. Patients with recurrent KSD post-parathyroidectomy were significantly younger compared to patients without recurrent KSD (51±15 vs. 60±13 years, p=0.02). In a logistic regression model, younger age remains a strong predictive factor for recurrent KSD. CONCLUSIONS Nearly a quarter of PHPT patients with KSD who undergo successful parathyroidectomy present with recurrent KSD despite normalization of serum calcium, and over half exhibit persistent calciuria. These patients were younger and may require closer monitoring for stone recurrence after successful parathyroidectomy. Further studies are needed to better identify the etiology of KSD post-parathyroidectomy. RATIONALE A substantial number of breast cancer patients with an overexpression of the human epidermal growth factor receptor 2 (HER2) have residual disease after neoadjuvant therapy or become resistant to trastuzumab. Photodynamic therapy (PDT) using nanobodies targeted to HER2 is a promising treatment option for these patients. Here we investigate the in vitro and in vivo antitumor efficacy of HER2-targeted nanobody-photosensitizer (PS) conjugate PDT. METHODS Nanobodies targeting HER2 were obtained from phage display selections. Monovalent nanobodies were engineered into a biparatopic construct. The specificity of selected nanobodies was tested in immunofluorescence assays and their affinity was evaluated in binding studies, both performed in a panel of breast cancer cells varying in HER2 expression levels. The selected HER2-targeted nanobodies 1D5 and 1D5-18A12 were conjugated to the photosensitizer IRDye700DX and tested in in vitro PDT assays. Mice bearing orthotopic HCC1954 trastuzumab-resistant tumors wD5-18A12-PS induced significant tumor regression of trastuzumab-resistant high HER2 expressing tumors, whereas in low HER2 expressing tumors only a slight growth delay was observed. CONCLUSION Nanobody-PS conjugates accumulated selectively in vivo and their fluorescence could be detected through optical imaging. Upon illumination, they selectively induced significant tumor regression of HER2 overexpressing tumors with a single treatment session. Nanobody-targeted PDT is therefore suggested as a new additional treatment for HER2-positive breast cancer, particularly of interest for trastuzumab-resistant HER2-positive breast cancer. Further studies are now needed to assess the value of this approach in clinical practice. Chemotherapy is an important modality available for cancer treatment. However, the present chemotherapy is still far from being satisfactory mainly owing to the severe side effects of the chemotherapeutic agents and drug resistance of cancer cells. Thus, reversing drug resistance by constructing an ideal chemotherapeutic strategy with the least side effects and the best efficacy is greatly needed. Here, we designed a smart nanosystem of thermo-sensitive liposome coated gold nanocages with doxorubicin (DOX) loading (LAD) for near-infrared (NIR)-triggered drug release and chemo-photothermal combination therapy. The biocompatible liposomes coating facilitated the cellular uptake of LAD and meanwhile avoided drug leakage during the circulation. More importantly, LAD exhibited controllable photothermal conversion property and produced mild heat under NIR irradiation, which not only triggered DOX release and transferred DOX from lysosome to nucleus, but also elicited the mild heat cell killing effect to improve the curative efficiency. Further mechanism study revealed that mild heat could reverse drug resistance by down-regulation of the chemoresistance-related markers (e.g., HSF-1, p53, P-gp), and inhibited DOX export and increased drug sensitiveness, thereby prominently increased the anticancer efficiency. This versatile nanoplatform with enhanced curative efficacy and lower side effect is promising to apply in the field of drug controlled release and combination tumor therapy. https://www.selleckchem.com/products/blu-285.html V.Conjugation of lipid moieties to nucleic-acid therapeutics increases their interaction with cellular membranes, enhances their uptake and influences in vivo distribution. Once injected in biological fluids, such modifications trigger the binding of various serum proteins, which in turn play a major role in determining the fate of oligonucleotides. Yet, the role played by each of these proteins, more than 300 in serum, remains to be elucidated. Albumin, the most abundant circulating protein is an attractive candidate to study, as it was previously used to enhance the therapeutic effect of various drugs. Herein, we present a thorough fluorescent-based methodology to study the effect of strong and specific albumin-binding on the fate and cellular uptake of DNA oligonucleotides. We synthesized a library of molecules that exhibit non-covalent binding to albumin, with affinities ranging from high (nanomolar) to none. Our results revealed that strong albumin binding can be used as a strategy to reduce degradation of oligonucleotides in physiological conditions caused by enzymes (nucleases), to reduce uptake and degradation by immune cells (macrophages) and to prevent non-specific uptake by cells.
