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1.
Phase II Clinical Trial of First-line Eribulin Plus Trastuzumab for Advanced or Recurrent HER2-positive Breast Cancer.
Sakaguchi, K, Nakatsukasa, K, Koyama, H, Kato, M, Sakuyama, A, Matsuda, T, Tsunoda, N, Fujiwara, I, Yamaguchi, M, Tanaka, H, et al
Anticancer research. 2018;(7):4073-4081
Abstract
BACKGROUND/AIM: Eribulin mesylate has been approved for advanced or metastatic breast cancers subjected to at least two previous chemotherapy regimens. The present multicenter, phase II, single-arm study assessed the efficacy and safety of a first-line regimen of eribulin plus trastuzumab for untreated advanced or metastatic HER2-positive breast cancer. PATIENTS AND METHODS Enrolled patients received eribulin (1.4 mg/m2 intravenously; I.V.) on days 1 and 8 of each 21-day cycle, an initial trastuzumab dose (8 mg/kg I.V.) on day 1, and 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. The primary endpoint was the response rate (RR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Twenty-eight patients (median age: 62.5 years) received a median of 12 (range: 2-53) cycles of eribulin plus trastuzumab. RESULTS The RR was 53.6% [complete response (CR), 4; partial response (PR), 11] with a median PFS of 344 days. The clinical benefit rate was 64.0%. Grade 3/4 adverse events were observed in 12 (42.9%) patients. For details, neutropenia in 8 (28.6%) patients, peripheral neuropathy in 2 (7.1%) patients, interstitial pneumonia in 1 (3.6%) patient, ALT elevation in 1 (3.6%) patient, osteonecrosis of the jaw in 1 (3.6%) patient, and fatigue in 1 (3.6%) patient. The patient with osteonecrosis received denosumab, too. No symptomatic congestive heart failure was observed. CONCLUSION Combination therapy of eribulin plus trastuzumab is acceptable in efficacy and safety, and a capable option for first-line advanced or recurrent HER2-positive breast cancer.
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2.
Titanium and polyether ether ketone (PEEK) patient-specific sub-periosteal implants: two novel approaches for rehabilitation of the severely atrophic anterior maxillary ridge.
Mounir, M, Atef, M, Abou-Elfetouh, A, Hakam, MM
International journal of oral and maxillofacial surgery. 2018;(5):658-664
Abstract
The aim of this study was to assess two new protocols for single-stage rehabilitation of the severely atrophic maxillary ridge using customized porous titanium or polyether ether ketone (PEEK) sub-periosteal implants. Ten patients with a severely atrophic anterior maxillary alveolar ridge were divided randomly into two groups (five patients in each) to receive customized sub-periosteal implants fabricated via CAD/CAM technology: group 1, porous titanium implants; group 2, PEEK implants. Prosthetic loading with fixed acrylic bridges was performed 1 month postoperative. The implants were followed-up for 12 months and evaluated for the presence of any sign of radiographic bone resorption, mobility, infection, prosthetic fracture, or implant exposure. The immediate postoperative period was uneventful except for one case complicated by wound dehiscence in group 1. At 12 months, all implants were functionally stable and the patients were comfortable with the prostheses. No signs of radiographic bone resorption, mobility, infection, or prosthetic fracture were observed. Within the limitations of this study, the application of customized porous titanium and PEEK sub-periosteal implants produced through CAD/CAM technology appears to be an acceptable method for single-stage prosthetic rehabilitation of the severely atrophic edentulous anterior maxilla. This study was awarded the best case study at the academy of osseintegration annual meeting 2017, Orlando, Florida.
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3.
Graphene-Oxide-Decorated Microporous Polyetheretherketone with Superior Antibacterial Capability and In Vitro Osteogenesis for Orthopedic Implant.
Ouyang, L, Deng, Y, Yang, L, Shi, X, Dong, T, Tai, Y, Yang, W, Chen, ZG
Macromolecular bioscience. 2018;(6):e1800036
Abstract
Due to its similar elastic modulus of human bones, polyetheretherketone (PEEK) has been considered as an excellent cytocompatible material. However, the bioinertness, poor osteoconduction, and weak antibacterial activity of PEEK limit its wide applications in clinics. In this study, a facile strategy is developed to prepare graphene oxide (GO) modified sulfonated polyetheretherketone (SPEEK) (GO-SPEEK) through a simple dip-coating method. After detailed characterization, it is found that the GO closely deposits on the surface of PEEK, which is attributed to the π-π stacking interaction between PEEK and GO. Antibacterial tests reveal that the GO-SPEEK exhibits excellent suppression toward Escherichia coli. In vitro cell attachment, growth, differentiation, alkaline phosphatase activity, quantitative real-time polymerase chain reaction analyses, and calcium mineral deposition all illustrate that the GO-SPEEK substrate can significantly accelerate the proliferation and osteogenic differentiation of osteoblast-like MG-63 cells compared with those on PEEK and SPEEK groups. These results suggest that the GO-SPEEK has an improved antibacterial activity and cytocompatibility in vitro, showing that the developed GO-SPEEK has a great potential as the bioactive implant material in bone tissue engineering.
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4.
Multi-axial damage and failure of medical grade carbon fibre reinforced PEEK laminates: Experimental testing and computational modelling.
Gallagher, EA, Lamorinière, S, McGarry, P
Journal of the mechanical behavior of biomedical materials. 2018;:154-167
Abstract
Orthopaedic devices using unidirectional carbon fibre reinforced poly-ether-ether-ketone (PEEK) laminates potentially offer several benefits over metallic implants including: anisotropic material properties; radiolucency and strength to weight ratio. However, despite FDA clearance of PEEK-OPTIMA™ Ultra-Reinforced, no investigation of the mechanical properties or failure mechanisms of a medical grade unidirectional laminate material has been published to date, thus hindering the development of first-generation laminated orthopaedic devices. This study presents the first investigation of the mechanical behaviour and failure mechanisms of PEEK-OPTIMA™ Ultra-Reinforced. The following multi-axial suite of experimental tests are presented: 0° and 90° tension and compression, in-plane shear, mode I and mode II fracture toughness, compression of ±45° laminates and flexure of 0°, 90° and ±45° laminates. Three damage mechanisms are uncovered: (1) inter-laminar delamination, (2) intra-laminar cracking and (3) anisotropic plasticity. A computational damage and failure model that incorporates all three damage mechanisms is developed. The model accurately predicts the complex multi-mode failure mechanisms observed experimentally. The ability of a model to predict diverse damage mechanisms under multiple loading directions conditions is critical for the safe design of fibre reinforced laminated orthopaedic devices subjected to complex physiological loading conditions.
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5.
Cold-induced metabolic conversion of haptophyte di- to tri-unsaturated C37 alkenones used as palaeothermometer molecules.
Kitamura, E, Kotajima, T, Sawada, K, Suzuki, I, Shiraiwa, Y
Scientific reports. 2018;(1):2196
Abstract
The cosmopolitan marine haptophyte alga Emiliania huxleyi accumulates very long-chain (C37-C40) alkyl ketones with two to four trans-type carbon-carbon double bonds (alkenones). These compounds are used as biomarkers of haptophytes and as palaeothermometers for estimating sea-surface temperatures in biogeochemistry. However, the biosynthetic pathway of alkenones in algal cells remains enigmatic, although it is well known that the C37 tri-unsaturated alkenone (K37:3) becomes dominant at low temperatures, either by desaturation of K37:2 or by a separate pathway involving the elongation of tri-unsaturated alkenone precursors. Here, we present experimental evidence regarding K37:3 synthesis. Using the well-known cosmopolitan alkenone producer E. huxleyi, we labelled K37:2 with 13C by incubating cells with 13C-bicarbonate in the light at 25 °C under conditions of little if any K37:3 production. After stabilisation of the 13C-K37:2 level by depleting 13C-bicarbonate from the medium, the temperature was suddenly reduced to 15 °C. The 13C-K37:2 level rapidly decreased, and the 13C-K37:3 level increased, whereas the total 13C-K37 level-namely [K37:2 + K37:3]-remained constant. These 13C-pulse-chase-like experimental results indicate that 13C-K37:2 is converted directly to 13C-K37:3 by a desaturation reaction that is promoted by a cold signal. This clear-cut experimental evidence is indicative of the existence of a cold-signal-triggered desaturation reaction in alkenone biosynthesis.
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6.
Incorporating Si3 N4 into PEEK to Produce Antibacterial, Osteocondutive, and Radiolucent Spinal Implants.
Pezzotti, G, Marin, E, Adachi, T, Lerussi, F, Rondinella, A, Boschetto, F, Zhu, W, Kitajima, T, Inada, K, McEntire, BJ, et al
Macromolecular bioscience. 2018;(6):e1800033
Abstract
Polyetheretherketone (PEEK) is a popular polymeric biomaterial which is primarily used as an intervertebral spacer in spinal fusion surgery; but it is developed for trauma, prosthodontics, maxillofacial, and cranial implants. It has the purported advantages of an elastic modulus which is similar to native bone and it can be easily formed into custom 3D shapes. Nevertheless, PEEK's disadvantages include its poor antibacterial resistance, lack of bioactivity, and radiographic transparency. This study presents a simple approach to correcting these three shortcomings while preserving the base polymer's biocompatibility, chemical stability, and elastic modulus. The proposed strategy consists of preparing a PEEK composite by dispersing a minor fraction (i.e., 15 vol%) of a silicon nitride (Si3 N4 ) powder within its matrix. In vitro tests of PEEK composites with three Si3 N4 variants-β-Si3 N4 , α-Si3 N4 , and β-SiYAlON-demonstrate significant improvements in the polymer's osteoconductive versus SaOS-2 cells and bacteriostatic properties versus gram-positive Staphylococcus epidermidis bacteria. These properties are clearly a consequence of adding the bioceramic dispersoids, according to chemistry similar to that previously demonstrated for bulk Si3 N4 ceramics in terms of osteogenic behavior (vs both osteosarcoma and mesenchymal progenitor cells) and antibacterial properties (vs both gram-positive and gram-negative bacteria).
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7.
Multiple modes of action of eribulin mesylate: Emerging data and clinical implications.
Cortes, J, Schöffski, P, Littlefield, BA
Cancer treatment reviews. 2018;:190-198
Abstract
Eribulin mesylate (eribulin) is a synthetic analogue of the marine-sponge natural product halichondrin B. Eribulin exhibits potent antiproliferative activities against a variety of human cancer cell types in vitro and in vivo, and is used for the treatment of certain patients with advanced breast cancer or liposarcoma who are refractory to other treatments. The antiproliferative effects of eribulin have long been attributed to its antimitotic activities. Unlike other microtubule-targeting agents, eribulin inhibits microtubule polymerization through specific plus end binding, thus interfering with microtubule dynamic instability. Non-mitotic effects of eribulin on tumor biology have also been established in laboratory settings including: tumor vasculature remodeling, increased vascular perfusion, reduced hypoxia, and phenotypic changes involving reversal of epithelial-to-mesenchymal transition (EMT), resulting in reduced capacities for migration, invasion, and seeding lung metastases in experimental models. Preclinical data suggest that increased perfusion following eribulin treatment improves delivery of subsequent drugs. Supporting evidence for eribulin's non-mitotic effects in the clinical setting include increased tumor oxygen saturation, reduced hypoxia, phenotype changes consistent with EMT reversal, and genotype changes consistent with shifts from nonendocrine-responsive, luminal B, to endocrine-responsive, luminal A, breast cancer subtypes. Finally, potential biomarkers for eribulin response have been established based on tumor-phenotype and gene-expression profiles. Overall, preclinical and clinical data support both antimitotic and non-mitotic mechanisms of eribulin that may underlie the survival benefit observed in various clinical trials.
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8.
A strategy to identify a ketoreductase that preferentially synthesizes pharmaceutically relevant (S)-alcohols using whole-cell biotransformation.
Haq, SF, Shanbhag, AP, Karthikeyan, S, Hassan, I, Thanukrishnan, K, Ashok, A, Sukumaran, S, Ramaswamy, S, Bharatham, N, Datta, S, et al
Microbial cell factories. 2018;(1):192
Abstract
INTRODUCTION Chemical industries are constantly in search of an expeditious and environmentally benign method for producing chiral synthons. Ketoreductases have been used as catalysts for enantioselective conversion of desired prochiral ketones to their corresponding alcohol. We chose reported promiscuous ketoreductases belonging to different protein families and expressed them in E. coli to evaluate their ability as whole-cell catalysts for obtaining chiral alcohol intermediates of pharmaceutical importance. Apart from establishing a method to produce high value (S)-specific alcohols that have not been evaluated before, we propose an in silico analysis procedure to predict product chirality. RESULTS Six enzymes originating from Sulfolobus sulfotaricus, Zygosaccharomyces rouxii, Hansenula polymorpha, Corynebacterium sp. ST-10, Synechococcus sp. PCC 7942 and Bacillus sp. ECU0013 with reported efficient activity for dissimilar substrates are compared here to arrive at an optimal enzyme for the method. Whole-cell catalysis of ketone intermediates for drugs like Aprepitant, Sitagliptin and Dolastatin using E. coli over-expressing these enzymes yielded (S)-specific chiral alcohols. We explain this chiral specificity for the best-performing enzyme, i.e., Z. rouxii ketoreductase using in silico modelling and MD simulations. This rationale was applied to five additional ketones that are used in the synthesis of Crizotinib, MA-20565 (an antifungal agent), Sulopenem, Rivastigmine, Talampanel and Barnidipine and predicted the yield of (S) enantiomers. Experimental evaluation matched the in silico analysis wherein ~ 95% (S)-specific alcohol with a chemical yield of 23-79% was obtained through biotransformation. Further, the cofactor re-cycling was optimized by switching the carbon source from glucose to sorbitol that improved the chemical yield to 85-99%. CONCLUSIONS Here, we present a strategy to synthesize pharmaceutically relevant chiral alcohols by ketoreductases using a cofactor balanced whole-cell catalysis scheme that is useful for the industry. Based on the results obtained in these trials, Zygosaccharomyces rouxii ketoreductase was identified as a proficient enzyme to obtain (S)-specific alcohols from their respective ketones. The whole-cell catalyst when combined with nutrient modulation of using sorbitol as a carbon source helped obtain high enantiomeric and chemical yield.
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Incidence and clinical parameters associated with eribulin mesylate-induced peripheral neuropathy.
Zhao, B, Zhao, H, Zhao, J
Critical reviews in oncology/hematology. 2018;:110-117
Abstract
Eribulin mesylate is a microtubule-targeting agent that has been approved for the treatment of breast cancer and liposarcoma. Due to its novel mechanism of action, eribulin therapy induces a distinct profile of adverse events, including peripheral neuropathy. However, the incidence and risk of eribulin-related neurotoxicities are unclear. Here, we conducted a systematic search of PubMed and Embase from their inception to October 2017. Eligible studies included trials in which eribulin was intravenously administered at a standard dose of 1.4 mg/m2 over 2-5 minutes on days 1 and 8 on a 21-day cycle. The events of all-grade and high-grade peripheral neuropathy were collected to calculate the overall incidence and relative risk (RR). A total of thirty-two studies containing 6129 subjects were included in this analysis. The incidences of all-grade and high-grade eribulin monotherapy-related peripheral neuropathy were 28% (95% confidence interval [CI], 24%-32%) and 4% (95% CI, 3%-5%), respectively. Subgroup analysis further revealed that a higher incidence of neurotoxicities was observed in patients with breast cancer and those with longer treatment duration. Moreover, eribulin-treated subjects had a significantly increased risk of all-grade (RR, 2.00; 95% CI, 1.70-2.35; p = 0.008) and high-grade (RR, 3.68; 95% CI, 2.30-5.89; p<0.001) neurotoxicities. Our results suggested that patients treated with eribulin had an increased risk of developing peripheral neuropathy.
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Subgroup analysis of patients with HER2-negative metastatic breast cancer in the second-line setting from a phase 3, open-label, randomized study of eribulin mesilate versus capecitabine.
Pivot, X, Im, SA, Guo, M, Marmé, F
Breast cancer (Tokyo, Japan). 2018;(3):370-374
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Abstract
This post hoc subgroup analysis of a large phase 3 study compared the efficacy and safety of eribulin versus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who received second-line treatment. In the phase 3 study, women with advanced/metastatic breast cancer and ≤ 3 prior chemotherapies were randomized 1:1 to eribulin mesilate 1.4 mg/m2 intravenously on days 1 and 8, or twice-daily oral capecitabine 1.25 g/m2 on days 1-14 (21-day cycles). This analysis included 392 patients. Median overall survival was longer in patients receiving eribulin compared with capecitabine (16.1 vs 13.5 months, respectively; HR 0.77, P = 0.026). Median progression-free survival and response rates were similar between arms. Both treatments had manageable safety profiles.