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Pharmaceutical multicomponent crystals (MCCs) including salts and co-crystals of active pharmaceutical ingredients (APIs), are an active focus of research to improve various physicochemical properties of drugs. In this work, we demonstrate that the pharmaceutical artesunate (AS), a derivative of artemisinin (ART), forms a 1 : 1 salt with two cinchona alkaloids: quinine (QN) and cinchonidine (CND), representing the first report of MCCs combining two major types of antimalarial drugs.

Many orally administered phenolic drugs undergo enterohepatic recycling (EHR), presumably mediated by the hepatic phase II enzymes. However, the disposition of extrahepatically generated phase II metabolites is unclear. This paper aims to determine the new roles of liver and intestine in the disposition of oral phenolics. Sixteen representative phenolics were tested using direct portal vein infusion and/or intestinal perfusion. The results showed that certain glucuronides were efficiently recycled by liver. OATP1B1/1B3/2B1 were the responsible uptake transporters. Hepatic uptake is the rate-limiting step in hepatic recycling. Our findings showed that the disposition of many oral phenolics is mediated by intestinal glucuronidation and hepatic recycling. A new disposition mechanism ‘Hepatoenteric Recycling (HER)”, where intestine is the metabolic organ and liver is the recycling organ, was revealed. Further investigations focusing on HER should help interpret how intestinal aliments or co-administered drugs that alter gut enzymes (e.g. UGTs) expression/activities will impact the disposition of phenolics.

Ibrutinib inhibits Bruton tyrosine kinase while venetoclax is a specific inhibitor of the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL), and clinical trials using the combination therapy have produced remarkable results in terms of rate of complete remission and frequency of undetectable minimal residual disease. However, the laboratory rationale behind the success of the drug combination is still lacking. A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. Using an ex vivo model that promotes CLL proliferation, we show that modeled ibrutinib proliferative responses, but not viability responses, correlate well with patients’ actual clinical responses. Importantly, we demonstrate for the first time that ibrutinib and venetoclax act on distinct CLL subpopulations that have different proliferative capacities. While the dividing subpopulation of CLL responds to ibrutinib, the resting subpopulation preferentially responds to venetoclax. The combination of these targeted therapies effectively reduced both the resting and dividing subpopulations in most cases. Our laboratory findings help explain several clinical observations and contribute to the understanding of tumor dynamics. Additionally, our proliferation model may be used to identify novel drug combinations with the potential of eradicating residual disease.

BackgroundThis study was conducted with the intent to develop and validate a radiomic model capable of predicting intrahepatic cholangiocarcinoma (ICC) in patients with intrahepatic lithiasis (IHL) complicated by imagologically diagnosed mass (IM).MethodsA radiomic model was developed in a training cohort of 96 patients with IHL-IM from January 2005 to July 2019. Radiomic characteristics were obtained from arterial-phase computed tomography (CT) scans. The radiomic score (rad-score), based on radiomic features, was built by logistic regression after using the least absolute shrinkage and selection operator (LASSO) method. The rad-score and other independent predictors were incorporated into a novel comprehensive model. The performance of the Model was determined by its discrimination, calibration, and clinical usefulness. This model was externally validated in 35 consecutive patients.ResultsThe rad-score was able to discriminate ICC from IHL in both the training group (AUC 0.829, sensitivity 0.868, specificity 0.635, and accuracy 0.723) and the validation group (AUC 0.879, sensitivity 0.824, specificity 0.778, and accuracy 0.800). Furthermore, the comprehensive model that combined rad-score and clinical features was great in predicting IHL-ICC (AUC 0.902, sensitivity 0.771, specificity 0.923, and accuracy 0.862).ConclusionsThe radiomic-based model holds promise as a novel and accurate tool for predicting IHL-ICC, which can identify lesions in IHL timely for hepatectomy or avoid unnecessary surgical resection.

Glucuronidation is one of the major metabolic pathways for flavonoids. However, quantification of flavonoid glucuronides in biological samples, especially in the bile, is sometimes challenging due to signal suppression by bile acids. The purpose of this study is to establish a robust LC-MS/MS method for directly measuring flavonoid glucuronides in bile and blood. Wogonoside (wogonin-7-O-glucuronide), baicalin (baicalein-7-O-glucuronide) and apigenin-7-O-glucuronide were used as the model compounds and taurocholic acid (T-CA) were used as the model bile acid to establish the method. Bile samples were processed using solid phase extraction (SPE) and blood samples were prepared using protein precipitation method. The analytes were separated on a Resteck HPLC (50 mm × 2.1 mm ID, 1.7 μm) column using acetonitrile and 0.1% formic acid in water as the mobile phases. The mass analysis was performed in an AB Sciex 5500 Qtrap mass spectrometer via multiple reaction monitoring (MRM) in the positive mode. The results showed that the linear range of the above three analytes were 10 nM–5000 nM in the bile and 1.56 nM–4000 nM in the blood, respectively. The recoveries of three glucuronides were> 85% and the matrix effects were 90% of these bile acids were removed by the selected SPE procedure to facilitate glucuronide analysis. The validated method was successfully applied to a portal vein infusion study using rats to quantify baicalin, wogonoside, and apigenin-glucuronide in bile and blood samples.

Fludarabine (flu) -containing regimens such as flu, cyclophosphamide and rituximab have been established as one of the standard first line therapy in medically-fit chronic lymphocytic leukemia (CLL) patients. Therefore, flu-refractory (primary flu-insensitivity or flu-caused relapse) remains a major problem causing treatment failure for CLL patients. We isolated the peripheral blood mononuclear cells (PBMCs) from CLL patients and treated with flu to find flu-refractory cases, and established flu-resistant clonal cells to study molecular mechanism of flu-resistance. By comparing parental MEC-2 cells, a human CLL cell line, we found that flu-resistant clonal cells were significantly increased lethal dose 50 of flu concentration, and up-regulated expression of P-glycoprotein, a drug-resistant marker, glucosylceramide synthase (GCS), an enzyme that can convert ceramide to glucosylceramide, and CD34, a leukemia stem cell marker. Overexpression of GCS leads to promptly elimination of cellular ceramide levels and accumulation of glucosylceramide, which reduces apoptosis and promotes survival and proliferation of flu-resistant clonal cells. Furthermore, we demonstrated that the accumulation of glucosylceramide can be blocked by PDMP to restore flu-sensitivity in flu-resistant clonal cells. We also found that elevating glucosylceramide levels in flu-resistant clonal cells was associated with up-regulation of GCS and CD34 expression. Importantly, overexpression of GCS or CD34 was also determined in flu-refractory PBMCs. Our results show that flu-resistance is associated with the alteration of ceramide metabolism and the development of leukemia stem cell-like cells. The flu-resistance can be reversed by GCS inhibition as a novel strategy for overcoming drug resistance.

Icaritin (ICT), a prenylflavonoid derivative extracted from the Epimedium genus, has exhibited antitumor effects in hepatocellular carcinoma (HCC) cells and safety and tolerance in clinical settings. However, ICT exhibits low blood concentration and the in vivo dominant plasma species of ICT is glucuronides [icaritin-3-glucuronide (G1), icaritin-7-glucuronide (G2) and icaritin-3, 7-diglucuronide (DIG)]. Therefore, how ICT reaches the liver and exerts its effect with low toxicity remains unknown. Therefore, pharmacokinetic experiments (p.o. 5 mg/kg with/out 50 mg/kg inhibitor combo), intestinal perfusion (2 μM ICT), portal vein infusion (1.6 μM ICT, 7.1 μM G1, 6.8 μM G2 and 4.4 μM DIG), and in vitro studies (the concentration range of substrates: 0.3–10 μM) were conducted in the present study. Ultimately, ICT was shown to undergo glucuronidation by the intestine and subsequent uptake by hepatocytes via organic anion transporting peptides (OATPs) as conjugates, followed by biliary excretion mainly as diglucuronide. In conclusion, we found for the first time that the intestine is considered as the major metabolic organ, liver as the main recycling organ for the enterohepatic recycling (EHR) of ICT. Moreover, DIG is the main species in the systemic circulation following oral administration of ICT which explains the low toxicity of ICT in clinical settings.

We investigated how human proislet peptide (HIP) regulates differentiation of human fetus–derived pancreatic progenitor cells (HFPPCs) and explored the potential link between HIP signaling and the menin pathway, which is key to regulating pancreatic islet differentiation. The data show that HIP promoted expression of proislet transcription factors (TFs), including PDX-1, MAFA, and NKX6.1, as well as other maturation markers of β-cells, such as insulin, GLUT2, KIR6.2, SUR1, and VDCC. Moreover, HIP increased insulin content and promoted the ability of HFPPCs to normalize blood glucose in diabetic mice. HIP inhibited the TF FOXO1 by increasing AKT-mediated phosphorylation. HIP-induced repression of FOXO1 suppressed menin expression, leading to reducing menin binding to the promoter of the three key proislet TFs, decreasing recruitment of H3K9 methyltransferase SUV39H1, and thus reducing repressive H3K9me3 at the promoter. These coordinated actions lead to increased expression of the proislet TFs, resulting in induction of HFPPC differentiation. Consistently, constitutive activation of FOXO1 blocks HIP-induced transcription of these TFs. Together, these studies unravel the crucial role of the HIP/AKT/FOXO/menin axis in epigenetically controlling expression of proislet TFs, regulating the differentiation of HFPPCs, and normalizing blood glucose in diabetic mice.

Glucuronidation is the most important phase II metabolic pathway which is responsible for the clearance of many endogenous and exogenous compounds. To better understand the elimination process for compounds undergoing glucuronidation and identify compounds with desirable in vivo pharmacokinetic properties, many efforts have been made to predict in vivo glucuronidation using in vitro data. In this article, we reviewed typical approaches used in previous predictions. The problems and challenges in prediction of glucuronidation were discussed. Besides that different incubation conditions can affect the prediction accuracy, other factors including efflux / uptake transporters, enterohepatic recycling, and deglucuronidation reactions also contribute to the disposition of glucuronides and make the prediction more difficult. PBPK modeling, which can describe more complicated process in vivo, is a promising prediction strategy which may greatly improve the prediction of glucuronidation and potential DDIs involving glucuronidation. Based on previous studies, we proposed a transport-glucuronidation classification system, which was built based on the kinetics of both glucuronidation and transport of the glucuronide. This system could be a very useful tool to achieve better in vivo predictions.

An LC-MS/MS method was developed and validated to determine 7α-OH cholesterol in liver microsome. This method was convenient and fast with high specificity and sensitivity. Briefly, a gradient elution was performed on a Synergi polar-C18 column (50 × 4.6 mm i.d., 3 µm). The mobile phase (consisting of 0.1% HCOOH solution and acetonitrile) eluted in gradient at a flow rate of 1 ml/min. MS detection was operated on APCI (+) mode; the MRM transitions for 7α-OH cholesterol and D7-cholesterol (I.S.) were 385.1 -> 159.1 and 376.4 -> 266.3, respectively. The linear response range of 7α-OH cholesterol was covered from 1.563 to 100.0 ng/ml. All of the validation items meet the requirement of FDA guidance for bioanalytical method validation. This method was applied to enzymatic studies for determination of cholesterol 7alpha-hydroxylation activity catalyzed by CYP7A1 in the cholestatic minipigs liver microsomes.

Background/aim Breast cancer is the most prevalent and devastating malignant disease among women worldwide. Green tea has been extensively studied for its anti-cancer effects, however, existing literature on the correlation of other types of tea with breast cancer is very limited. Materials and methods We used six different breast cancer cell lines (ER+, PR+ or HER2+ and triple-negative), treated under different concentrations of green, oolong, black and dark tea extracts, and determined their biological effects. Results We determined cell viability, observed the changes of cell morphology, measured DNA damage and cleavage, and analyzed the effect on soft agar colony formation and growth. Conclusion Oolong tea, same as green tea, can induce DNA damage and cleavage, play an inhibitory role in breast cancer cell growth, proliferation and tumorigenesis, and was a great potential as a chemo-preventive agent against breast cancer.

Alteration of lipid metabolism plays a critical role in the development of many types of cancer including breast cancer. Lipid metabolism can be regulated by a variety of signaling pathways with proliferative stimuli, apoptotic stimuli or environment changes under physiological, pathophysiological or therapeutic conditions. On the other hand, many lipids and lipid intermediate metabolites are also important signaling molecules involved in cell signaling that regulate cell proliferation, differentiation, apoptosis and migration as well as responses to drug treatment. In physiological condition, lipid metabolism (anabolism and catabolism) is tightly regulated by signaling network in the cell under designed path to growth, proliferation, differentiation and migration. Dysregulation of lipid metabolism under pathological condition leads to alteration of lipid profiles and accumulation of some “bad” lipids which can cause cell overgrowth and hyper-proliferation such as cancer and cell death such as tissue injury (Fig. 8.3). This chapter focuses on the emerging understanding of the role of lipid metabolic pathway in breast carcinogenesis and tumor progression. The update information indicates that the modulation of lipid metabolism can potentially be exploited to prevent breast cancer and enhance efficacy of breast cancer therapy.

The purpose of this study was to develop and validate a robust and sensitive LC–MS/MS method for simultaneous determinations of various tyrosine kinase inhibitors (TKIs) in biological samples and to apply the method to their pharmacokinetic studies. Processed samples were injected into the UHPLC system coupled to an ESI-triple quadrupole mass spectrometer. The compounds were separated on an AcQuity UHPLC BEH C18 column (50 mm × 2.1 mm ID, 1.7 μm) using a gradient elution of acetonitrile/0.1% formic acid in water. The mass analysis was performed in an API 3200 Qtrap mass spectrometer via selective reaction monitoring operated under a positive scanning mode. The method was validated over a linear range of 3.13–800 nM for erlotinib; 6.25–1600 nM for sunitinib, pazopanib, and axitinib; and 12.5–3200 nM for sorafenib, dasatinib, lapatinib, and nilotinib, respectively. The intra-day and inter-day precision were

Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway for many compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces: the formation of glucuronides by UGT enzymes and the (polarized) excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that although UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure.

Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling and gene transcription. Vorinostat is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing HDAC6 and Hsp90 client proteins. Fifty-five patients with clinical stage IIA-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m(2)) plus vorinostat (200-300 mg PO BID) on days 1-3 of each paclitaxel dose plus trastuzumab (for Her2/neu positive disease only), followed by doxorubicin/cyclophosphamide (60/600 mg/m(2) every 2 weeks plus pegfilgrastim). The primary study endpoint was pathologic complete response (pCR). pCR occurred in 13 of 24 evaluable patients with Her2-positive disease (54, 95 % confidence intervals [CI] 35-72 %), which met the prespecified study endpoint. pCR occurred in 4 of 15 patients with triple negative disease (27, 95 % CI 11-52 %) and none of 12 patients with ER-positive, Her2/neu negative disease (0, 95 % CI 0-24 %), which did not meet the prespecified endpoint. ER-positive tumors exhibited lower Ki67 and higher Hsp70 expression, and HDAC6, Hsp70, p21, and p27 expression were not predictive of response. Vorinostat increased acetylation of Hsp90 and alpha tubulin, and reduced expression of Hsp90 client proteins and HDAC6 in the primary tumor. Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin-cyclophosphamide is associated with a high pCR rate in locally advanced Her2/neu positive breast cancer. Consistent with cell line and xenograft data, vorinostat increased acetylation of Hsp90 and alpha tubulin, and decreased Hsp90 client protein and HDAC6 expression in human breast cancers in vivo.

Ibrutinib (Ibr) is a specific inhibitor of Bruton tyrosine kinase, a component of the B-cell receptor (BCR) signaling. Venetoclax (Veneto) inhibits the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL) (Byrd NEJM, Roberts, NEJM, 2015 and Roberts, Blood, 2019) and clinical trials using the combination therapy are ongoing. An interesting clinical observation is that the tumor cell sensitivity to these two drugs differ between different anatomic compartments. While lymph node-resident CLL cells are more sensitive to ibr, circulating CLL cells in the peripheral blood are more sensitive to the action of veneto. When these two drugs are used in combination to treat relapsed/refractory (Hillman ASH 2018 and Kater EHA 2019) or previously untreated CLL patients (Jain NEJM 2019), rate of complete response significantly increases compared to single drug alone. Moreover, negativity of bone marrow minimal residual disease continues to improve over time. However, the reason behind these observed compartmental responses is largely unknown, and we investigated the differential response using an ex vivo model that promotes CLL proliferation (CLL proliferation model). A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. We established the ex vivo model using fibroblasts derived from the bone marrow of a CLL patient. In this model, CLL cells closely interact with the bone marrow fibroblasts (BMF) (Fig.1) and divide and proliferate for several generations, as measured by CFSE labeling. The culture, in some cases, may continue for 10 weeks before cell death ensues. With this ability to promote long-term cell proliferation, the model recapitulates one of the most salient features observed histologically in the "proliferation centers" of the CLL lymph nodes. With the proliferation model, we first tested the effects of ibrutinib on cell division/proliferation as well as cell viability in samples taken from 30 CLL patients consisting of 22 ibr-naïve (thus sensitive) and 8 ibr-relapsed (thus resistant) patients. We demonstrate that there was lack of a significant inhibition of ibr on cell viability. In comparison, Ibr markedly inhibited cell proliferation in cells from ibr-naïve/sensitive patients (p With the CLL proliferation model, we also evaluated how veneto works. Veneto, as expected, markedly decreased cell viability at clinically achievable concentrations. CFSE profiles of the remaining live cells, however, revealed an interesting pattern of distribution, showing that veneto induces cell death but it preferentially kills the resting CLL population (Fig. 2). In other words, the resting subpopulation of CLL, instead of the dividing one, preferentially responds to veneto as compared to ibr. Combination of the two drugs, as expected, worked most effectively, significantly reducing the total number of live cells, both resting and dividing subpopulations, in all cases. Analyses of CFSE profiles became less meaningful in many of these cases due to the small number of live cells remaining after the combination treatment. In conclusion, our study, comparing the actions of ibr and veneto in a clinically relevant CLL proliferation model, demonstrates for the first time that the drugs target distinct subpopulations of CLL cells with different proliferative capacity. The data also suggest that single drug therapy may leave a subpopulation behind that would potentially rise to cause a future relapse. Our study provides a strong laboratory rationale explaining why combining these two drugs has the potential to eradicate CLL disease. The findings are also in line with the clinical observations regarding the compartmental response; ibrutinib works primarily on the lymph nodes where CLL cells divide in the "proliferation centers" and veneto acts preferentially on the circulating CLL cells that are mostly non-dividing and resting. Disclosures Wang: Incyte Reaserch Institute: Employment. Ma:Abbvie: Research Funding; Xeme: Research Funding; Novartis: Research Funding; Bioverativ: Consultancy; Janssen: Consultancy, Speakers Bureau; Beigene: Research Funding; Kite: Consultancy; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy; Incyte: Research Funding; Juno: Research Funding. Larson:Celgene: Consultancy; Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials.

By taking advantage of the excessively upregulated expression of neuropilin (NRP) on the surface of both glioma cells and endothelial cells of angiogenic blood vessels, the ligand of NRP with high affinity - tLyp-1 peptide, which also contains a CendR motif ((R/K)XX(R/K)), was functionalized to the surface of PEG-PLA nanoparticles (tLyp-1-NP) to mediate its tumor homing, vascular extravasation and deep penetration into the glioma parenchyma. The tLyp-1-NP was prepared via a maleimide-thiol coupling reaction with uniformly spherical shape under TEM and particle size of 111.30 ± 15.64 nm. tLyp-1-NP exhibited enhanced cellular uptake in both human umbilical vein endothelial cells and Rat C6 glioma cells, increased cytotoxicity of the loaded PTX, and improved penetration and growth inhibition in avascular C6 glioma spheroids. Selective accumulation and deep penetration of tLyp-1-NP at the glioma site was confirmed by in vivo imaging and glioma distribution analysis. The longest survival was achieved by those mice bearing intracranial C6 glioma treated with PTX-loaded tLyp-1-NP. The findings here strongly indicate that tLyp-1 peptide-functionalized nanoparticulate DDS could significantly improve the efficacy of paclitaxel glioma therapy.

The development of a drug delivery strategy which can mediate efficient tumor targeting together with high cellular internalization and extensive vascular extravasation is essential and important for glioma treatment. To achieve this goal, F3 peptide that specifically bind to nucleolin, which is highly expressed on the surface of both glioma cells and endothelial cells of glioma angiogenic blood vessels, is utilized to decorate a nanoparticulate drug delivery system to realize glioma cell and neovasculature dual-targeting and efficient cellular internalization. Tumor homing and penetrating peptide, tLyp-1 peptide, which contains the motif of (R/K)XX(R/K) and specially binds to neuropilin is co-administrated to improve the penetration of the nanoparticles across angiogenic vasculature into glioma parenchyma. The F3 conjugation via a maleimide-thiol coupling reaction was confirmed by XPS analysis with 1.03% nitrogen detected on the surface of the functionalized nanoparticles. Enhanced cellular interaction with C6 cells, improved penetration in 3D multicell tumor spheroids, and increased cytotoxicity of the loaded paclitaxel were achieved by the F3-functionalized nanoparticles (F3-NP). Following co-administration with tLyp-1 peptide, F3-NP displayed enhanced accumulation at the tumor site and deep penetration into the glioma parenchyma and achieved the longest survival in mice bearing intracranial C6 glioma. The findings here clearly indicated that the strategy by co-administrating a tumor homing and penetrating peptide with functionalized nanoparticles dual-targeting both glioma cells and neovasculature could significantly improve the anti-glioma drug delivery, which also hold a great promise for chemotherapy of other hard-to-cure cancers.

Objectives: The aim of our study is to assess the frequency of detection of PET positive CT negative skeletal metastases (SM) and determine the impact of such detection on staging and/or management in patients who had FDG PET/CT as part of the cancer work up. Methods: We retrospectively reviewed 2000 18F-FDG PET/CT scans of known cancer patients. A log was kept to record cases of suspected SM with or without bone changes from the low-dose non-contrast CT. The presence or absence of SM was evaluated based on available pathological and clinical data. The impact of detection of such lesions on cancer staging and/or management was evaluated by a board certified oncologist. Results: Of the 2000 cases, 18F-FDG PET/CT suggested SM in 146/2000 (7.3%). Of those 146 cases, 105 (72%) were positive on both PET and CT. The remaining 41 (28%) had PET positive CT negative bone lesions. SM was confirmed in 36/41 (88%) PET positive/CT negative cases. This was based on biopsy, imaging or clinical follow-up. The detection of PET positive CT negative SM did not change staging or management in 7/36 (19.4%). However, staging and/or management was affected in 29/36 (80.6%). Conclusions: SM is not uncommon in 18F-FDG PET/CT, as it accounts for 146/2000 (7.3%) of cases. PET demonstrated FDG-avid SM without a CT abnormality in at least 36/146 (25%). Patients staging and or management changed in 29/36 (80.5%). We concluded that 18F-FDG PET is sensitive in detection of SM with significant impact on staging & or management. Key words 18F-FDG PET/CT, Skeletal metastasis, PET positive, CT negative

Nanoparticulate drug delivery system possesses distinct advantages for brain drug delivery. However, its amount that reach the brain is still not satisfied. Cell-penetrating peptides (CPPs), short peptides that facilitate cellular uptake of various molecular cargo, would be appropriate candidates for facilitating brain delivery of nanoparticles. However, such effect could be deprived by the rapid systemic clearance of CPPs-functionalized nanoparticles due to their positive surface charge. Penetratin (CPP with relatively low content of basic amino acids) was here functionalized to poly(ethylene glycol)-poly(lactic acid) nanoparticles (NP) to achieve desirable pharmacokinetic and biodistribution profiles for brain drug delivery. The obtained penetratin-NP showed a particle size of 100 nm and zeta potential of -4.42 mV. The surface conjugation of penetratin was confirmed by surface chemical compositions analysis via X-ray photo electron spectroscopy. In MDCK-MDR cell model, penetratin-NP presented enhanced cellular accumulation via both lipid raft-mediated endocytosis and direct translocation processes with the involvement of Golgi apparatus, lysosome and microtubules. In vivo pharmacokinetic and biodistribution studies showed that penetratin-NP exhibited a significantly enhanced brain uptake and reduced accumulation in the non-target tissues compared with low-molecular-weight protamine (CPP with high arginine content)-functionalized nanoparticles. These data strongly implicated that penetratin-NP might represent a promising brain-targeting drug delivery system. The findings also provided an important basis for the optimization of brain drug delivery systems via surface charge modulation.

A novel β-NaCaPO 4 containing borate glass-ceramic is prepared. Two porous glass-ceramic scaffolds are prepared by binding particles with the size of 200–300 μm by 5 wt.% sodium silicate solution and 2 wt.% chitosan solutions, respectively. The reaction of the scaffolds in the SBF solution is characterized by weight loss analysis, XRD, FTIR, and SEM. The same is done to the 45S5 glass scaffolds as comparison. XRD and FTIR indicate that the carbonate hydroxyapatite has formed more rapidly on the borate glass-ceramic scaffolds. The carbonated hydroxyapatite depositing on chitosan binding scaffolds has lower crystallization degree than that on sodium silicate binding scaffolds and is similar to that of the human bone, which makes the chitosan binding scaffolds a good potential prospect in the field of tissue engineering.

A borophosphate glass with the mol% composition 25Na2O-25CaO-5P2O3-45B2O5 was melted. The crystalline phase rheanite crystallized spontaneously during cooling the sample. Porous glass-ceramic scaffolds were prepared by bonding glass particles with size distributions in the range of approximately 100–500 μm by 0.1 M Na2SiO3 solutions. The scaffolds porosities were 40 ~ 60% and their compressive strengths were 0.1 ~ 0.4 MPa. The conversion of the binding scaffolds to hydroxyapatite (HA) was investigated by measuring the weight loss after soaking the sample in a solution of 0.25 M K2HPO4 with a pH value of 9.0 at 37 °C as a function of time. Hydroxyapatite (HA) was observed by XRD and SEM after soaking for 7 days. Cell attachment, spreading and proliferation on both unconverted scaffolds and on scaffolds coated with HA were determined by MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] assay method using Murine osteoblastic-like MC3T3-E1 cells. The scaffolds are biocompatible and their biocompatibility is enhanced after the formation of a HA layer.

e22078Background: While diabetes is known to worsen breast cancer outcomes, little is known about the effect of breast cancer on diabetes. Patients with breast cancer are frequently administered cy...

8 Background: While diabetes is known to worsen breast cancer (BC) outcomes, little is known about the effect of BC on diabetes outcomes. This study examined differences in outcomes diabetic patients with and without a history of BC. Methods: Data from NHANES 2010 – 2016 was used to identify female patients self-reporting diabetes mellitus (DM). Comparisons of DM outcomes for persons reporting a history of BC versus without any cancer were made using Chi-Square and separate analyses were conducted for younger (less than 65) and older (65 and older) respondents. Analyses were conducted using SAS survey procedures (Cary, NC) and were weighted to account for the sampling scheme. Results: The analytic cohort consisted of 1347 patients, of which 80 (6.3%, weighted) reported a history of breast cancer. 785 (62.4%, weighted) of the full sample was under age 65. Of those under 65, 3% (weighted) reported history of BC and 11.8% (weighted) of those over 65% reported BC. In diabetics under 65, respondents with BC were more likely to report physical limitations keep them from working and physical, mental, and emotional limitations (p = .001, and p = 0.03, respectively) and were less likely to use insulin (p = .01) than respondents without BC. In respondents 65 and older, women with BC were more likely to report problems with memory and confusion (p = .002) and less likely to rate their general health as excellent or very good (p = .01) compared to those without BC. No differences were found for demographic characteristics, retinopathy, heart disease, or stroke for either age group. Conclusions: In this population of patients with diabetes, history of BC was associated with physical and emotional limitations in younger patients and general health status and memory and confusion in older patients. Understanding the intersection of multiple chronic conditions is important for improving quality of life and clinical outcomes in BC survivors.

Diverse compounds from many different chemical classes are currently targeted in preclinical analyses for their ability to act as both chemopreventive and chemotherapeutic agents. Phenolic phytochemicals from Rhodiola crenulata has such potential. This Rhodiola species is a perennial plant that grows in the Tundra, Siberia, and high-elevation regions of Tibet. The phenolic secondary metabolites isolated from R. crenulata were recently analyzed in a preclinical setting for their ability to treat lymphosarcomas and superficial bladder cancers. However, the effects of R. crenulata have yet to be examined for its implications in breast cancer prevention or for its chemotherapeutic abilities. Therefore this study investigated the effects of R. crenulata on breast cancer both in vivo and in vitro. Experiments using aggressive human-derived MDA-MB-231 and mouse-derived V14 breast cancer cell lines demonstrated that phenolic-enriched R. crenulata extract was capable of inhibiting the proliferation, motility, and invasion of these cells. In addition, the extracts induced autophagic-like vesicles in all cell lines, eventually leading to death of the tumor cell lines but not the immortal or normal human mammary epithelial cells. Finally, an in vivo experiment showed that phenolic-enriched dietary R. crenulata is effective in preventing the initiation of tumors and slowing down the tumor growth in mice bearing tumor grafts, thereby further demonstrating its possible potential for treatment of breast cancer progression and metastasis.

The influence of solid-solution temperature on the dissolution of carbide precipitates, the average grain size and the micro-hardness of the austenite matrix in an Fe-Ni based high strength low thermal expansion (HSLTE) alloy was investigated to obtain the proper temperature range of the solid-solution process. The XRD analysis, microstructure observations, and the theoretical calculations showed that the Mo-rich M 2 C-type precipitates in the Fe-Ni based HSLTE alloy dissolve completely at about 1100°C. The average grain size of the studied alloys increases from 14 to 46 μm in the temperature range of 1050 to 1200°C. The microhardness of the matrix decreases first for the sake of solid-solution treatment, but then increases later with increasing solution temperature because of the solution strengthening effect.

Using KClO3 as an inner oxidant, MnZn-ferrite powder was synthesized by a self-propagating high-temperature synthesis (SHS) process in normal air atmosphere. The effects of the inner oxidant on combustion temperature, combustion velocity, microstructure and the phase of the product were investigated by XRD and SEM, respectively. The results show that a highly ferritized powder can be obtained as well as the highest combustion temperature and the highest combustion velocity when the inner oxidant content m equals 5/4 (k – 1/6).

An early full-term pregnancy significantly reduces the risk of getting breast cancer in women. In animals, this protection can be mimicked by a short-term exposure to physiologic doses of estrogen plus progesterone. Sensitization of p53 and up-regulation of transforming growth factor β are believed to be important aspects of the mechanism by which protection is imparted. Little is known, however, about the use of this pathway in response to other chemopreventive agents. In this article, we investigated the ability of retinoids, such as 9-cis retinoic acid, all-trans retinoic acid, and N-4-hydroxyphenylretinamide (4-HPR), to sensitize the ductal epithelial cells of virgin mammary glands to DNA damage responses. Using a whole-organ culture system, we observed enhanced cell death in response to γ-irradiation in the virgin tissues treated with retinoids for 72 hours. These retinoids were partially dependent on p53 and transforming growth factor β to exert their radiosensitizing effects. However, 4-HPR seemed to sensitize other cells or activate these pathways in a different manner as costimulation with ovarian hormones and 4-HPR was additive, whereas coculture of ovarian hormones and the natural retinoids did not increase amount of death. Taken together, these data suggest that sensitization of the mammary epithelium to p53-dependent apoptosis is a common pathway, which is engaged by retinoids as well as ovarian hormones.

115 Background: The elderly population is the fastest growing segment of the US population, and it is widely affected by cancer and its related sequelae. At St. Louis University (SLU), a simple Rapid Geriatric Assessment (RGA) was developed based on the SLU Mental Status Exam (SLUMS). The RGA includes screening for frailty, sarcopenia, nutrition, and cognition. In this pilot study, we used RGA to assess geriatric patients with newly diagnosed malignancy prior to cancer therapy and its ability to improve outcomes in oncology patients. Methods: Elderly patients (aged 65 and above) with newly diagnosed malignancy completed the RGA either inpatient or outpatient at SLU. A retrospective chart review was done to collect patient's demographics, type of malignancy, number of hospitalizations since diagnosis and referral to palliative care over a 6 month period. Relationship between tolerability and RGA subscores were assessed using general linear models, Kaplan-Meier survival analysis and Chi-square testing. Results: Twenty six patients (mean age 76 [65-90]) were included from December 2015 to 2016 of which 9 were male (n = 35) and 17 female (n = 65). 19 patients (73%) were inpatient, 7 (27%) were outpatient and 13 patients (50%) received chemotherapy. Using the Mann-Whitney U test, no significant difference was seen between RGA subscores (FRAIL p = 1; SNAQ p = 0.69; SARC-F p = 0.71; RCS p = 1) in patients receiving versus not receiving chemotherapy. There was no significant difference in overall survival (OS) over a 20 month period based on chemotherapy status (p = 0.39). In our study, 62% of patients (n = 16) were referred to palliative care and noted to have a significant better OS (p = 0.04). Conclusions: The RGA is a self-explanatory tool that can be used in geriatric oncology patients and it can bedone in 10 minutes. In this pilot study, we used this tool in a small number of patients. We plan to perform a prospective study to evaluate the RGA comparing to ECOG-performance status in geriatric patients prior to standard cancer therapies. Improvement of overall survival with incorporation of palliative care in oncology patients is reaffirmed in our study.

44 Background: Recent research shows tele-health and remote access technology enhances patient-provider communication. Among oncology patients, studies demonstrate that electronic access promotes improved treatment adherence and symptom management and provides better continuity of care and patient satisfaction. In a previous audit, we found only 26% of our oncology patients had activated our EHR (EPIC) online patient portal. MyChart facilitates communication by allowing patients to see results and email providers through a secure network. We undertook this study to discover patient opinions about MyChart and barriers to wider adoption. Methods: A short, self-administered questionnaire was distributed to a convenience sample of patients in waiting areas or the infusion center of the outpatient oncology clinic. Results: 76/108 patients knew of MyChart; 32 did not. 54/76 (71.1%) of patients who knew of MyChart had used it. 81.5% of 54 users were very or somewhat satisfied with it. Users rated features of MyChart on a 5 point scale: certain their confidentiality is protected 4.7,ability to track tests 4.4,receiving faster answers 3.0,and ease of contacting providers 2.8. 21 non-users gave several reasons for not using MyChart: preference to speak with a live person 38.1%, discomfort with the internet 23.8%, not having internet 19.0%, concern about personal information on the internet 14.3%, and too complicated 9.5%. Among 32patients not previously aware of MyChart, 43.7% said they would definitely or probably start using it.56.3% thought MyChart would make it easier to contact providers and 53.1%cited convenience over telephone.However, 28.1%,preferred speaking to a live person; 12.5% were uncomfortable with the internet, and 9.4% expressed concern with their information on the internet. Conclusions: In this sample, 50% of respondents used MyChart. Patients using MyChart were generally satisfied, specifically with confidentiality and ability to monitor their care. Barriers to increased use included a desire to speak directly to providers and lack of internet skill or access. While those using MyChart were confident that it was secure and confidential, those not using expressed concern about this issue.

Hispanic women have higher breast cancer mortality compared to non-Hispanic whites. We evaluated for Proliferation Axis Score differences, as determined by Oncotype Dx, in Hispanic and non-Hispanic white women with newly diagnosed breast cancer. We matched 219 women, based upon age, stage, and nodal status. Compared to non-Hispanic whites, Hispanic women with hormone-sensitive, HER2-negative early-stage breast cancer had a higher Proliferation Axis Score. No differences were seen in Recurrence Score, ER, PR, or HER2 by Oncotype DX. CCNB1 and AURKA were significantly higher in Hispanic women. These tumor differences may help explain breast cancer outcome differences between the two ethnicities.

Antiangiogenic therapy shows great advantages in clinical cancer treatment while no overall survival has been achieved. The compromised results were mainly contributed by intrinsic/acquired antiangiogenic drug resistance and increased local invasion or distant metastasis after antiangiogenic therapy. Here we constructed a CGKRK peptide-modified PEG-co-PCL nanoparticulate drug delivery system (DDS), aiming at targeting both tumor angiogenic blood vessels and tumor cells to achieve enhanced anti-tumor activity as well as holding a great potential to overcome the drawbacks of antiangiogenic therapy alone. The obtained CGKRK-functionalized PEG-co-PCL nanoparticles (CGKRK-NP) with a particle size of 117.28 ± 10.42 nm and zeta potential of -15.7 ± 3.32 mV, exhibited an enhanced accumulation via an energy-dependent, lipid raft/caveolae-mediated endocytosis with the involvement of microtubules in human umbilical vein endothelial cells (HUVEC) and an energy-dependent, lipid raft/caveolae-mediated endocytosis with the participation of Golgi apparatus in human U87MG cells. Using coumarin-6 as the fluorescence probe, in vitro U87MG tumor spheroids assays showed that CGKRK-NP effectively penetrated into the tumor spheroids. Selective accumulation and extensive bio-distribution of CGKRK-NP at tumor site was confirmed by in vivo imaging and tumor section analysis. After drug loading, CGKRK-NP enhanced cytotoxicity and apoptosis induction activity of the loaded PTX on both HUVEC cells and U87MG cells and improved its inhibition effect on the growth of U87MG tumor spheroids. The smallest tumor volume was achieved by those mice bearing subcutaneous U87MG tumor following the treatment of PTX-loaded CGKRK-NP. The findings here indicated that CGKRK peptide-functionalized nanoparticulate DDS could be used as an effective tumor angiogenic blood vessels and tumor cells dual-targeting DDS and might provide a great promising approach for reducing the disadvantages of antiangiogenic therapy alone.

The blood-brain barrier (BBB), which is formed by the brain capillary wall, greatly hinders the development of new drugs for the brain. Over the past decades, among the various receptor-mediated endogenous BBB transport systems, the strategy of using transferrin or anti-transferrin receptor antibodies to facilitate brain drug delivery system is of particular interest. However, the application of large proteins still suffers from the drawbacks including synthesis procedure, stability, and immunological response. Here, we explored a B6 peptide discovered by phase display as a substitute for transferrin, and conjugated it to PEG-PLA nanoparticles (NP) with the aim of enhancing the delivery of neuroprotective drug across the BBB for the treatment of Alzheimer's disease. B6-modified NP (B6-NP) exhibited significantly higher accumulation in brain capillary endothelial cells via lipid raft-mediated and clathrin-mediated endocytosis. In vivo, fluorescently labeled B6-NP exhibited much higher brain accumulation when compared with NP. Administration of B6-NP encapsulated neuroprotective peptide-NAPVSIPQ (NAP)-to Alzheimer's disease mouse models showed excellent amelioration in learning impairments, cholinergic disruption, and loss of hippocampal neurons even at lower dose. These findings together suggested that B6-NP might serve as a promising DDS for facilitating the brain delivery of neuropeptides.

Based on the powerful cell-penetrating ability of low molecular weight protamine (LMWP) and the overexpression of matrix metalloproteinases in the tumor sites, we constructed an activatable low molecular weight protamine (ALMWP) and modified it onto the surface of poly(ethylene glycol)-poly(lactic acid) nanoparticles to develop a "smart" drug delivery system with enhanced permeability for facilitating site-specific targeting delivery of anticancer drug. The obtained ALMWP-functionalized nanoparticles (ALMWP-NP) with a particle size of 134.0 ± 4.59 nm and a zeta potential of -34.4 ± 2.7 mV, exhibited an enhanced MMP-dependent accumulation in HT-1080 cells via both energy-independent direct translocation and clathrin-mediated, cytoskeleton-dependent endocytosis. Pharmacokinetic and biodistribution study in HT-1080 tumor-bearing mice showed that ALMWP-NP significantly increased the accumulation of paclitaxel (PTX) in the tumor site but not the nontarget tissues. In addition, intratumor distribution analysis demonstrated that more ALMWP-NP penetrated deeply into the tumor parenchyma. As a result, PTX loaded by ALMWP-NP exhibited improved antitumor efficacy over that by unmodified nanoparticles and LMWP-functionalized nanoparticles. The findings suggested that ALMWP-NP could be used as a safe and effective tumor-targeting drug delivery system and opened a new gateway to the application of cell-penetrating peptides for targeted antitumor therapy.