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Figure S1: Endocrine-resistant MCF-7 cells demonstrate sensitivity to TRAIL Figure S2: Endocrine-resistant CSCs demonstrate sensitivity to TRIAL. Figure S3: Primary-derived patient samples. Figure S4: Endocrine-resistant primary and PDX tumour cells are sensitive to TRAIL. Figure S5: Mechanism of endocrine-resistant tumour cell sensitivity to TRAIL.

Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer.Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumors.Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo. In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP.Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential. Clin Cancer Res; 24(10); 2452–63. ©2018 AACR.

Supplementary Information from Targeting Focal Adhesion Kinase with Dominant-Negative FRNK or Hsp90 Inhibitor 17-DMAG Suppresses Tumor Growth and Metastasis of SiHa Cervical Xenografts

Supplementary Figures 1-9 from Targeting Focal Adhesion Kinase with Dominant-Negative FRNK or Hsp90 Inhibitor 17-DMAG Suppresses Tumor Growth and Metastasis of SiHa Cervical Xenografts

Background Pectoralis minor syndrome involves pain, paraesthesia and weakness in the arm due to compression of the brachial plexus passing beneath pectoralis minor; this paper reports the results of a single centre’s treatment pathway in affected patients. Methods During a four-year period, patients exhibiting symptoms of pectoralis minor syndrome without significant improvement following physiotherapy proceeded to Botulinum injection. Those with good response to injection but subsequent recurrence of symptoms were offered pectoralis minor tenotomy. Oxford shoulder Scores were collected at baseline and after interventions. Results Twenty-one patients received Botulinum injection; at six weeks following injection, mean change in Oxford Shoulder Score was +12.4, with only one patient reporting a worsening of symptoms. Of the 17 patients with clinically significant response to injection, 12 have subsequently undergone tenotomy; three months following tenotomy, mean change in Oxford Shoulder Score from baseline was +22.3. Improvement was maintained in all patients at prolonged follow-up (average 20 months post-tenotomy). Discussion This pathway has shown to be extremely effective in patients not responding to first-line treatment for pectoralis minor syndrome, with 85% of patients post-injection and 100% of patients post-tenotomy showing significant (greater than published minimal clinically important difference value of six points) improvements in Oxford Shoulder Score, maintained at follow-up.

Proteins, as a major component of organisms, are considered the preferred biomaterials for drug delivery vehicles. Hemoglobin (Hb) has been recently rediscovered as a potential drug carrier, but its use for biomedical applications still lacks extensive investigation. To further explore the possibility of utilizing Hb as a potential tumor targeting drug carrier, we examined and compared the biodistribution of Hb in healthy and lung tumor-bearing mice, using for the first time 89Zr labelled Hb in a positron emission tomography (PET) measurement. Hb displays a very high conjugation yield in its fast and selective reaction with the maleimide-deferoxamine (DFO) bifunctional chelator. The high-resolution X-ray structure of the Hb-DFO complex demonstrated that cysteine β93 is the sole attachment moiety to the αβ-protomer of Hb. The Hb-DFO complex shows quantitative uptake of 89Zr in solution as determined by radiochromatography. Injection of 0.03 mg of Hb-DFO-89Zr complex in healthy mice indicates very high radioactivity in liver, followed by spleen and lungs, whereas a threefold increased dosage results in intensification of PET signal in kidneys and decreased signal in liver and spleen. No difference in biodistribution pattern is observed between naïve and tumor-bearing mice. Interestingly, the liver Hb uptake did not decrease upon clodronate-mediated macrophage depletion, indicating that other immune cells contribute to Hb clearance. This finding is of particular interest for rapidly developing clinical immunology and projects aiming to target, label or specifically deliver agents to immune cells.

ISSN 1758-1923 Breast Cancer Manage. (2014) 3(3), 237–240 Q What led you to specialize in the field of breast cancer stem cell research? It was almost by accident. Approximately 6 years ago, two of my graduate students, Alison Wakefield and Luke Piggott, decided to share resources and expertise. Alison had adopted a relatively new technique described by Dontu et al. that enriched for cancer stem cells in an attempt to quantify cancer stem cells in our mouse models of breast cancer [1]. Meanwhile, Luke was investigating ways to sensitize human breast cancer cells to a new and promising therapeutic agent called TRAIL. Luke tried the cancer stem cell assay out on his system – in a ‘suck-it-and-see’ experiment. The results were astounding, and virtually overnight my laboratory turned its attentions to the question of targeting breast cancer stem cells as a therapeutic strategy. This, I believe, demonstrates the importance of academic freedom in scientific research and the benefits of providing a structured, yet creative, environment for talented young researchers to interact.

The essential oils from Commiphora species have for centuries been recognized to possess medicinal properties. Here, we performed gas chromatography-mass spectrometry on the essential oil from opoponax (Commiphora guidotti) and identified bisabolene isomers as the main constituents of this essential oil. Opoponax essential oil, a chemical component; β-bisabolene and an alcoholic analogue, α-bisabolol, were tested for their ability to selectively kill breast cancer cells. Only β-bisabolene, a sesquiterpene constituting 5% of the essential oil, exhibited selective cytotoxic activity for mouse cells (IC50 in normal Eph4:200 µg/ml, MG1361: 65.49 µg/ml, 4T1: 48.99 µg/ml) and human breast cancer cells (IC50 in normal MCF-10A: 114.3 µg/ml, MCF-7: 66.91 µg/ml, MDA-MB-231: 98.39 µg/ml, SKBR3: 70.62 µg/ml and BT474: 74.3 µg/ml). This loss of viability was because of the induction of apoptosis as shown by Annexin V-propidium iodide and caspase-3/7 activity assay. β-bisabolene was also effective in reducing the growth of transplanted 4T1 mammary tumours in vivo (37.5% reduction in volume by endpoint). In summary, we have identified an anti-cancer agent from the essential oil of opoponax that exhibits specific cytotoxicity to both human and murine mammary tumour cells in vitro and in vivo, and this warrants further investigation into the use of β-bisabolene in the treatment of breast cancers.

The knowledge, beliefs and experience of 60 women with HRT was studied when the women were premenopausal, and 10 years later when they were postmenopausal. Thirty-eight women had taken HRT by 1993. In 1993 women no longer considered clinics and self help groups to be the most useful sources of information about the menopause. They were more likely to think that doctors' knowledge of HRT was not adequate and to favour the use of HRT. Their reservations about all postmenopausal women receiving HRT continued. The women's understanding of long-term use of HRT varied. The women continued to maintain a desire not to experience withdrawal bleeding with HRT. More than 60% of women considered that HRT helped hot flushes, non-specific emotional changes and vaginal dryness. Women in 1993 were more likely to consider that HRT would help the menopausal symptoms of osteoporosis, insomnia and loss of muscle tone while fewer considered anxiety and depression would be relieved by HRT. Only one third believed HRT would reduce the incidence of heart disease. Women were more likely to take or have taken HRT if they were working and had achieved a higher work status (professional), considered reading material as the most useful source of information about menopause, had experienced menopause symptoms as distressing, considered menopause made relationships with husband and children more difficult and supported the universal use of HRT for all women.

Following spinal cord injury, profound vascular changes lead to ischemia and hypoxia of spinal cord tissue. Since fibroblast growth factor 2 (FGF2) has angiogenic effects, its delivery to the injured spinal cord may attenuate the tissue damage associated with ischemia. To limit systemic mitogenic effects, FGF2 was delivered to the spinal cord via a gel of hyaluronan and methylcellulose (HAMC) injected into the intrathecal space, and compared to controls receiving HAMC alone and artificial cerebrospinal fluid (aCSF) alone. Dynamic perfusion computed tomography (CT) was employed for the first time in small animals to serially measure blood flow and permeability in the injured and uninjured spinal cord. Spinal cord blood flow (SCBF) and permeability-surface area (PS) measurements were obtained near the injury epicenter, and at two regions rostral to the epicenter in animals that received a 26-g clip compression injury. As predicted, SCBF measurements decreased and PS increased after injury. FGF2 delivered via HAMC after injury restored SCBF towards pre-injury values in all regions, and increased blood flow rates at 7 days post-injury compared to pre-injury measurements. PS was stabilized at regions rostral to the epicenter of injury when FGF2 was delivered with HAMC, with significantly lower values than aCSF controls at 7 days in the region farthest from the epicenter. Laminin staining for blood vessels showed a qualitative increase in vessel density after 7 days when FGF2 was locally delivered. Additionally, permeability stains showed that FGF2 moderately decreased permeability at 7 days post-injury. These data demonstrate that localized delivery of FGF2 improves spinal cord hemodynamics following injury, and that perfusion CT is an important technique to serially measure these parameters in small animal models of spinal cord injury.

We present the results of real-time reflection terahertz time-domain spectroscopy (THz-TDS) measurements of flowing powders. The data shows a clear relationship between the sizes of particles flowing through a tube to measured scattering losses at terahertz frequencies. The particle size of the powder covers the range of typical length-scales used in the pharmaceutical and food industry.

This paper reports a study of the spontaneous precipitation of calcium carbonate from aqueous solutions which are very supersaturated with respect to calcite, both in the absence of inhibitors, and in the presence of triphosphate as inhibitors. The sequence of events during precipitation is governed strongly by the initial supersaturation, the temperature, and the presence or absence of triphosphate.At high supersaturation, the first-formed phase is an amorphous calcium carbonate. It is observed only above a well defined ionic activity product, is homogeneously nucleated, and its formation is not inhibited by triphosphate. Over the temperature range 289–333 K, this amorphous phase has a solubility product, K1, defined by the equation: log K1=(1247.0/T)– 10.224, At concentrations insufficient to produce the amorphous phase, the first-formed solid nucleates heterogeneously. In the absence of triphosphate it is calcite. In the presence of triphosphate, the first solid is calcium carbonate hexahydrate at lower temperatures, and a vaterite/calcite mixture at higher temperatures. CaCO3·6H2O is formed only at temperatures below ca. 25 °C, and decomposes to vaterite. These crystalline phases also result from the decomposition of the amorphous CaCO3 at higher initial supersaturation.In the course of the work, the solubility product for CaCO3·6H2O (K2) was measured in the range 277–312 K as: log K2=(1696/T)+ 0.9336 The quantitative basis of the study was consistent with a re-evaluation of the CaCO03 pair constant K3, as: log K3= 7.722 –(1347.2/T). These results show that at temperatures below 25 °C the binding of CO2–3 to calcium is significantly greater than earlier publications have suggested: the implication for the distribution of carbonate species in the oceans has yet to be fully assessed.

The title compounds exist in pH-dependent equilibrium between cation and ring-opened anion; since pK 2 1 , the hypothetical neutral species is always metastable.

Gibbsite, lithiophorite, pyrolusite, and goethite, plus discrete mixtures of gibbsite and lithiophorite and of gibbsite and iron oxide, occur as replacement veins in limestone. Minor accessories are barite, alunite, opal. Minerals of wall-rock alteration are garnet, idocrase, K-feldspar, prehnite, sericite, and quartz. These silicates formed at higher temperature than the vein minerals, but the whole sequence is considered to be a product of the same solutions, of deep-seated origin, deposited over a long period of time.

A short and practical alternative synthesis of the Corey aldehyde (2), a key intermediate in prostaglandin synthesis, is described. 6-Acetoxyfulvene (7) underwent a Diels–Alder reaction with 2-chloroacrylonitrile to give 7-acetoxymethylene-2-chlorobicyclo[2.2.1]hept-5-ene-2-carbonitrile (8) which was converted sequentially into 2-chloro-7-anti-formylbicyclo[2.2.1]hept-5-ene-2-carbonitrile (10) and its 7-syn-isomer (11). The factors controlling the stereochemistry at C(7) in the anti- and syn-aldehydes (10) and (11) are discussed in detail.