Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic ...breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer.
This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0–2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival.
Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9–22), median progression-free survival was 20·1 months (95% CI 14·2–21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1–17·0) in the capecitabine group (hazard ratio 0·659 95% CI 0·437–0·994, one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 75% of 92 vs 14 16% of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred.
Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen.
Pfizer, Shinpoong, and Daewoong Korea and Takeda.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Selective blockade of nociceptive neurons can be achieved by the delivery of permanently charged sodium channel blockers through the pores of nociceptive ion channels. To assess the feasibility of ...this application in the dental area, we investigated the electrophysiological and neurochemical characteristics of nociceptive dental primary afferent (DPA) neurons. DPA neurons were identified within trigeminal ganglia labeling with a retrograde fluorescent dye applied to the upper molars of adult rats. Electrophysiological studies revealed that the majority of dental primary afferent neurons showed characteristics of nociceptive neurons, such as sensitivity to capsaicin and the presence of a hump in action potential. Immunohistochemical analysis revealed a large proportion of DPA neurons to be IB4-positive and to express TRPV1 and P2X3. Single-cell RT-PCR revealed mRNA expression of various nociceptive channels, including the temperature-sensitive TRPV1, TRPA1, TRPM8 channels, the extracellular ATP receptor channels P2X2 and P2X3, as well as the nociceptor-specific sodium channel, NaV1.8. In conclusion, DPA neurons have the electrophysiological characteristics of nociceptors and express several nociceptor-specific ion channels. Analysis of these data may assist in the search for a new route of entry for the delivery of membrane-impermeant local anesthetics. Abbreviations: AP, action potential; DiI, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate; DPA, dental primary afferent; FITC, fluorescein 5(6)-isothiocyanate; IB4, isolectin-B4; RT-PCR, reverse-transcription polymerase chain-reaction; TRP, transient receptor potential.
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CMK, NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Background
Both vertebrobasilar dolichoectasia (VBD) and cerebral microbleeds (CMBs) are related with the risk of intracerebral hemorrhage. We aimed to examine the relationship between the VBD and ...CMB in ischaemic stroke patients.
Methods
A consecutive series of 182 patients hospitalized because of ischaemic stroke or transient ischaemic attack (TIA), and who underwent gradient echo brain magnetic resonance imaging were retrospectively recruited from a prospective stroke registry. CMB locations were categorized into anterior and posterior circulation. Ectasia was defined as basilar artery (BA) diameter > 4.5 mm, and dolichosis, as either BA bifurcation above the suprasellar cistern or lateral to the margin of the clivus or dorsum sellae. Whether VBD is associated with CMB anywhere in the brain or in anterior or posterior circulation territories was analysed using binary and multinomial logistic regression models.
Results
Twenty‐four subjects (13.2%) had VBD and 48 (26.4%) had CMBs. CMBs were more frequently observed in patients with VBD than without (66.7% vs. 20.3%, P < 0.001). VBD was significantly associated with CMBs in any location (crude odds ratio, 7.88; 95% confidence interval, 3.10–20.02), in the posterior circulation territory only (9.63; 2.60–34.94), and in both territories (9.25; 3.40–26.29), but not in the anterior circulation only (1.14; 0.009–11.20). These associations remained unchanged after adjusting for age, gender, hypertension, leukoaraiosis and stroke subtype.
Conclusions
VBD in patients with ischaemic stroke or TIA is independently associated with CMBs, especially in the posterior circulation territory.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms ...leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3'-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR-29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
There is a need for effective wound healing through rapid wound closure, reduction of scar formation, and acceleration of angiogenesis. Hydrogel is widely used in tissue engineering, but it is not an ...ideal solution because of its low vascularization capability and poor mechanical properties. In this study, gelatin methacrylate (GelMA) was tested as a viable option with tunable physical properties. GelMA hydrogel incorporating a vascular endothelial growth factor (VEGF) mimicking peptide was successfully printed using a three-dimensional (3D) bio-printer owing to the shear-thinning properties of hydrogel inks. The 3D structure of the hydrogel patch had high porosity and water absorption properties. Furthermore, the bioactive characterization was confirmed by cell culture with mouse fibroblasts cell lines (NIH 3T3) and human umbilical vein endothelial cells. VEGF peptide, which is slowly released from hydrogel patches, can promote cell viability, proliferation, and tubular structure formation. In addition, a pig skin wound model was used to evaluate the wound-healing efficacy of GelMA-VEGF hydrogel patches; the results suggest that the GelMA-VEGF hydrogel patch can be used for wound dressing.
See also Mutch NJ. Polyphosphate scores a hat trick in regulating host defense mechanisms. This issue, pp 1142–4.
Summary.
Background: Recent results have indicated that polyphosphate, released by ...activated platelets, can function as a procoagulant to modulate the proteolytic activity of serine proteases of the blood clotting cascade.
Objective: To determine whether polyphosphate is involved in inducing signal transduction in cellular and animal models.
Methods: The effect of polyphosphate on human umbilical vein endothelial cells was examined by monitoring cell permeability, apoptosis and activation of NF‐κB after treating cells with different concentrations of polyphosphate. Moreover, the expression of cell surface adhesion molecules (VCAM‐1, ICAM‐1 and E‐selectin) and the adhesion of THP‐1 cells to polyphosphate‐treated cells were monitored using established methods. In the in vivo model, the pro‐inflammatory effect of polyphosphate was assessed by monitoring vascular permeability and migration of leukocytes to the peritoneal cavity of mice injected with polyphosphate.
Results: Polyphosphate, comprised of 45, 65 and 70 phosphate units, enhanced the barrier permeability and apoptosis in cultured endothelial cells and up‐regulated the expression of cell adhesion molecules, thereby mediating the adhesion of THP‐1 cells to polyphosphate‐treated endothelial cells. These effects of polyphosphate were mediated through the activation of NF‐κB and could not be recapitulated by another anionic polymer, heparin. Polyphosphate also increased the extravasation of the bovine serum albumin (BSA)‐bound Evans blue dye and the migration of leukocytes to the mouse peritoneal cavity, which was prevented when activated protein C (APC) was intravenously (i.v.) injected 2 h before the challenge.
Conclusion: Polyphosphate, in addition to up‐regulation of coagulation, can elicit potent pro‐inflammatory responses through the activation of NF‐κB, possibly contributing to the pro‐inflammatory effect of activated platelets.
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FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The toxicity of the antifouling biocides Irgarol 1051, Diuron, Chlorothalonil, Dichlofluanid, Sea-nine 211, Copper pyrithione, Zinc pyrithione, Ziram and Zineb were evaluated on Nitzschia pungens and ...Artemia larvae. Results showed that EC50 for Irgarol 1051 was 0.586μgl−1 was the strongest effect on N. pungens following by Copper pyrithione (4.908μgl−1), Ziram (5.421μgl−1), Zinc pyrithione (5.513μgl−1), Diuron (6.640μgl−1), Zineb (232.249μgl−1), Sea-nine 211(267.368μgl−1), Chlorothalonil (360.963μgl−1) and Dichlofluanid (377.010μgl−1) in 96h. In Artemia larvae, the biocides were evaluated the LC50 for larval survivals at 48h. Sea-nine 211 and Copper pyrithione were 0.318 and 0.319mgl−1. Chlorothalonil, Zinc pyrithione and Ziram were 2.683, 3.147 and 4.778mgl−1. Irgarol 1051, Diuron, Zineb and Dichlofluanid were 9.734, 30.573, 41.170 and 154.944mgl−1. These results provide baseline data concerning the toxicity of antifouling biocides against marine environment.
•Nine antifouling biocides were investigated toxicological response•Two species (Nitzschia pungens and Artemia larvae) were used to assess•Results showed comparable for ecological risk using antifouling paint
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Background
Bacterial flagellin, a Toll‐like receptor 5 agonist, is used as an adjuvant for immunomodulation. In this study, we aimed to evaluate the effect and its mechanism following intralymphatic ...administration of OVA‐flagellin (FlaB) mixture in the mouse model of allergic rhinitis.
Materials and Methods
BALB/c mice were sensitized with OVA and treated with an OVA‐FlaB mixture via intranasal, sublingual, and intralymphatic routes to evaluate the effect of each treatment. Several parameters for allergic inflammation and its underlying mechanisms were then evaluated.
Results
Intralymphatic injection of the OVA‐FlaB mixture reduced symptom scores, eosinophil infiltration in the nasal mucosa, and total and OVA‐specific IgE levels more significantly than intranasal and sublingual administration. Systemic cytokine (IL‐4, IL‐5, IL‐6, IL‐17, and IFN‐γ) production and local cytokine (IL‐4 and IL‐5) production were also reduced significantly after intralymphatic injection with OVA‐FlaB. Double intralymphatic injection of the mixture was more effective than single injection. Moreover, the expression of innate cytokines such as IL‐25 and IL‐33 in nasal epithelial cells was reduced, and the expression of chemokines such as CCL24 (eotaxin‐2), CXCL1, and CXCL2 was decreased in the nasal mucosa, suggesting the underlying mechanism for intralymphatic administration of the OVA‐FlaB mixture.
Conclusion
Intralymphatic administration of an OVA‐FlaB mixture was more effective in alleviating allergic inflammation than intranasal and sublingual administration in a mouse model of allergic rhinitis. This effect may be attributed to the reduced expression of innate cytokines and chemokines. This treatment modality can be considered as a new therapeutic method and agent.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cold pressed avocado oil was microencapsulated by spray drying in four different wall systems consisting of whey protein isolate (WPI) alone or in combination with maltodextrin (MD) DE 5 at various ...ratios (90 : 10, 50 : 50 and 10 : 90). The WPI only or WPI/MD (90 : 10) powders were spherical and smooth, whereas the WPI/MD (50 : 50 and 10 : 90) powders exhibited pronounced surface collapse. Increasing the MD ratio resulted in higher bulk density and wettability, probably due to more compact physical structure and hydrophilic wall matrix. Surface free oil contents and microencapsulation efficiencies of powders were 11-16% and 45-66%, respectively, and no significant differences were observed between the samples. The crude avocado oil used in this study appeared to be stable against oxidation at cold and ambient temperatures, irrespective of microencapsulation. However, at high temperature of 60°C, the oxidative stability decreased significantly in all cases but it was improved to some extent by microencapsulation.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective: To evaluate the impact of neurological and medical complications on 3‐month outcomes in acute ischaemic stroke patients.
Methods: We prospectively investigated complications for all the ...consecutive acute ischaemic stroke patients admitted within 7 days from onset in four university hospitals during a 1‐year period. Baseline data and 3‐month outcomes were collected. Poor outcome was defined as a modified Rankin Scale score 3–6.
Results: A total of 1 254 patients were recruited: 264 (21.1%) and 303 (24.2%) patients experienced one or more neurological and medical complications, respectively. The most common complications were ischaemic stroke progression (17.1%) and pneumonia (12.0%). Of 1 233 patients with available 3‐month outcomes, 34.9% had a poor outcome. Multivariate analysis revealed that neurological (odds ratio, 95% confidence interval; 5.47, 3.63–8.24) and medical (3.47, 2.30–5.23) complications were independent predictors of the poor outcome. For the individual complications, ischaemic stroke progression (7.48, 4.73–11.84), symptomatic hemorrhagic transformation (3.57, 1.33–9.54), pneumonia (4.44, 2.20–8.99), extracranial bleeding (4.45, 1.88–10.53), and urinary tract infection (2.72, 1.32–5.60) were independently associated with the poor outcome.
Conclusion: Outcome after ischaemic stroke is adversely influenced by complications, especially ischaemic stroke progression, symptomatic hemorrhagic transformation, pneumonia, extracranial bleeding, and urinary tract infection. Interventions to prevent those complications might improve ischaemic stroke outcome.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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