Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia

Bruton's tyrosine kinase (BTK) is a cytoplasmic protein found in all hematopoietic cell lineages except for T cells. BTK mediates signalling downstream of a number of receptors. Pharmacological targeting of BTK using ibrutinib (previously PCI-32765) has recently shown encouraging clinical activity in a range of lymphoid malignancies. This study reports for the first time that ibrutinib inhibits blast proliferation from human acute myeloid leukaemia (AML) and that treatment with ibrutinib significantly augmented cytotoxic activities of standard AML chemotherapy cytarabine or daunorubicin. Here we describe that BTK is constitutively phosphorylated in the majority of AML samples tested, with BTK phosphorylation correlating highly with the cell's cytotoxic sensitivity towards ibrutinib. BTK targeted RNAi knock-down reduced colony forming capacity of primary AML blasts and proliferation of AML cell lines. We showed ibrutinib binds at nanomolar range to BTK. Furthermore, we also showed ibrutinib's anti-proliferative effects in AML are mediated via an inhibitory effect on downstream nuclear factor-κB (NF-κB) survival pathways. Moreover, ibrutinib inhibited AML cell adhesion to bone marrow stroma. Furthermore, these effects of ibrutinib in AML were seen at comparable concentrations efficacious in chronic lymphocytic leukemia (CLL). These results provide a biologic rationale for clinical evaluation of BTK inhibition in AML patients

Humidity resistant fabrication of CH3NH3PbI3 perovskite solar cells and modules

A humidity resistant and versatile fabrication method for the production of very high quality, organic-inorganic perovskite films, solar cells and solar modules is presented. By using ethyl acetate as an anti-solvent during deposition, perovskite solar cells with power conversion efficiencies (PCEs) up to 15% were fabricated in a 75% relative humidity (RH) environment. Ethyl acetate acts as a moisture absorber during spin-coating, protecting sensitive perovskite intermediate phases from airborne water during film formation and annealing. We have demonstrated the manufacture of 50 mm x 50 mm series interconnected modules with PCEs in excess of 10% for 13.5 cm2 devices processed in air at 75%RH and 11.8% at 50%RH. To the best of our knowledge, these results represent the highest efficiency for perovskite solar modules processed under high humidity ambient conditions. This new deposition protocol allows for low-cost, efficient and consistent device fabrication in humid climates and uncontrolled laboratories

Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential

The Karyopherin superfamily is a major class of soluble transport receptors consisting of both import and export proteins. The trafficking of proteins involved in transcription, cell signalling and cell cycle regulation among other functions across the nuclear membrane is essential for normal cellular functioning. However, in cancer cells, the altered expression or localization of nuclear transporters as well as the disruption of endogenous nuclear transport inhibitors are some ways in which the Karyopherin proteins are dysregulated. The value of nuclear transporters in the diagnosis, prognosis and treatment of cancer is currently being elucidated with recent studies highlighting their potential as biomarkers and therapeutic targets

Small molecule inhibitors of CRM1

The transport through the nuclear pore complex is used by cancer cells to evade tumor-suppressive mechanisms. Several tumor-suppressors have been shown to be excluded from the cell nucleus in cancer cells by the nuclear export receptor CRM1 and abnormal expression of CRM1 is oncogenic. Inhibition of CRM1 has long been postulated as potential approach for the treatment of cancer and to overcome therapy resistance. Furthermore, the nuclear export of viral components mediated by the CRM1 is crucial in various stages of the viral lifecycle and assembly of many viruses from diverse families, including coronavirus. However, the first nuclear export inhibitors failed or never entered into clinical trials. More recently CRM1 reemerged as a cancer target and a successful proof of concept was achieved with the clinical approval of Selinexor. The chemical complexity of natural products is a promising perspective for the discovery of new nuclear export inhibitors with a favorable toxicity profile. Several screening campaigns have been performed and several natural product-based nuclear export inhibitors have been identified. With this review we give an overview over the role of CRM1-mediated nuclear export in cancer and the effort made to identify and develop nuclear export inhibitors in particular from natural sources.This work was supported by Fundação para a Ciência e a Tecnologia (FCT) Research Center Grant UID/BIM/04773/2013 Centre for Biomedical Research 1334 and by the Spanish Ministry of Science, Innovation and Universities through Grant RTI2018-094629-B-I00 to WL. BF was supported by FCT-SFRH/BPD/100434/2014 and Marie Curie Individual Fellowship project TRIBBLES (#748585). This work was also supported by two LPCC-NRS/Terry Fox grants (2016/2017; 2017/2018).info:eu-repo/semantics/publishedVersio

Keratan sulfate, a complex glycosaminoglycan with unique functional capability

From an evolutionary perspective keratan sulfate (KS) is the newest glycosaminoglycan (GAG) but the least understood. KS is a sophisticated molecule with a diverse structure, and unique functional roles continue to be uncovered for this GAG. The cornea is the richest tissue source of KS in the human body but the central and peripheral nervous systems also contain significant levels of KS and a diverse range of KS-proteoglycans with essential functional roles. KS also displays important cell regulatory properties in epithelial and mesenchymal tissues and in bone and in tumor development of diagnostic and prognostic utility. Corneal KS-I displays variable degrees of sulfation along the KS chain ranging from non-sulfated polylactosamine, mono-sulfated and disulfated disaccharide regions. Skeletal KS-II is almost completely sulfated consisting of disulfated disaccharides interrupted by occasional mono-sulfated N-acetyllactosamine residues. KS-III also contains highly sulfated KS disaccharides but differs from KS-I and KS-II through 2-O-mannose linkage to serine or threonine core protein residues on proteoglycans such as phosphacan and abakan in brain tissue. Historically, the major emphasis on the biology of KS has focused on its sulfated regions for good reason. The sulfation motifs on KS convey important molecular recognition information and direct cell behavior through a number of interactive proteins. Emerging evidence also suggest functional roles for the poly-N-acetyllactosamine regions of KS requiring further investigation. Thus further research is warranted to better understand the complexities of KS

大学ｽﾎﾟｰﾂ選手に対する実践的栄養教育

ｽﾎﾟｰﾂ選手の競技力向上に関して､食事管理が重要であることは認識されつつあるが､選手自身による食事管理は難しく栄養素等の過不足を起こしていることが多い｡選手自身による食事管理能力の修得と､実践的栄養教育に必要な内容の明確化を目的として､大学ﾊﾞﾚｰﾎﾞｰﾙ･空手道選手に栄養教育を伴う調理実習を行い､知識､技術､意識に関するｱﾝｹｰﾄ調査を行った｡結果は､5段階評価の｢そう思う､ややそう思う､どちらともいえない､あまりそう思わない､そう思わない｣を､順に｢5､4､3､2､1点｣として評価した｡その結果､評価平均値は空手群における知識面に関する1つの項目を除き､4を超えており高い評価が得られ､ｽﾎﾟｰﾂ選手自身による食事管理への寄与が示唆された｡Dietary management is important for athletes in order to improve their performance. However, such management is difficult for them, and they often take nutrients in inappropriate amounts. We herein provided athletes with nutrition education involving cooking practice, with the aim of developing their skills for dietary management, and clarifying the contents needed for practical nutrition education. University volleyball players and karate practitioners received nutrition education, and were administered a questionnaire inquiring about their knowledge, skills, and awareness in order to determine the effects of the education. The question items were scored on a 5-point grading scale: the answers “I agree”, “I slightly agree”, “no applicable answer”, “I slightly disagree”, and “I disagree” equaled 5, 4, 3, 2, and 1 point, respectively. For all question items, except for 1 knowledge-related item, karate practitioners showed an average of >4 points, suggesting the beneficial effects of nutrition education for athletes\u27 dietary management

大学男女空手道選手の栄養素等摂取状況および身体的特徴

本研究の目的は､ﾄｯﾌﾟﾚﾍﾞﾙの大学空手道選手を男女別に分類し､栄養素等摂取状況､身体的特徴について検討することである｡対象はN大学空手道部員22名(男子13名､女子9名)と習慣的な運動を有さない男女大学生27名(男子7名､女子20名)である｡空手群はｺﾝﾄﾛｰﾙ群に比較して､男女共に body mass index(BMI)と除脂肪量(LBM)が有意に高く､女子群は身長､体重､体脂肪量､腹囲も有意に高かった｡適正量に対する栄養素等摂取量の割合は､女子群がﾋﾞﾀﾐﾝ B1､B2 を除いて適正量を満たしておらず､男子群においてはどの項目も満たしていなかった｡肉類以外のたんぱく質源(豆類､魚介類､卵類)は､それぞれの目標量を50%も満たしておらず､たんぱく質源の摂取に偏りがみられた｡The aim of this study was to examine the nutrient intake and anthropometric characteristics of top-class university karate athletes by gender. The study involved 22 karate athletes(13 men and 9 women)who participated in N university student karate club and 27 university students(7 men and 20 women)without exercise habits. Both men and women in the karate group had a significantly higher body mass index(BMI)and lean body mass(LBM)than those in the control group, and the female athletes had a significantly greater height, body weight, fat mass, and waist circumference than their counterparts. When examined as a percentage of the dietary reference intake(DRI), nutrient intake of the female athletes did not meet the DRIs for all nutrients except for vitamins B1 and B2, while the male athletes failed to achieve the DRIs for all nutrients. These athletes had less than 50% of the target intake of non-meat protein sources(beans, fish/seafood, and eggs), indicating an unbalanced intake of different sources of protein

Engineering thermosensitive liposome-nanoparticle hybrids loaded with doxorubicin for heat-triggered drug release

The engineering of responsive multifunctional delivery systems that combine therapeutic and diagnostic (theranostic) capabilities holds great promise and interest. We describe the design of thermosensitive liposome-nanoparticle (NP) hybrids that can modulate drug release in response to external heating stimulus. These hybrid systems were successfully engineered by the incorporation of gold, silver, and iron oxide NPs into the lipid bilayer of lysolipid-containing thermosensitive liposomes (LTSL). Structural characterization of LTSL-NP hybrids using cryo-EM and AFM revealed the incorporation of metallic NPs into the lipid membranes without compromising doxorubicin loading and retention capability. The presence of metallic NPs in the lipid bilayer reinforced bilayer retention and offered a nanoparticle concentration-dependent modulation of drug release in response to external heating. In conclusion, LTSL-NP hybrids represent a promising versatile platform based on LTSL liposomes that could further utilize the properties of the embedded NPs for multifunctional theranostic applications