Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action

The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative, as well as estrogen receptor-positive, breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells, suggesting its mechanism of action differs from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds, as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.     

Erfahrungen bei der zerstörenden Abbrandbestimmung von Reaktorbrennelementen

Es werden zerstörende Abbranduntersuchungen beschrieben, die auf der Analyse des Gehalts der aktiven Spaltprodukte ¹³⁷Cs und ⁹⁰Sr, des stabilen ¹⁴⁸Nd, des Urans sowie auf der Isotopenzusammensetzung des Urans beruhen. Die Erfahrungen bei der Abtrennung und Bestimmung dieser Komponenten unter Anwendung säulenchromalographischer Methoden (lonenaustausch, Extraktionschromatographie; Trennschemata werden angegeben) aus Kernbrennstoff der Reaktoren WWRS und WWER werden mitgeteilt. Die Ergebnisse der einzelnen Methoden, ihre Übereinstimmung sowie ein Vergleich mit theoretischen Berechunungen werden diskutiert.     

微观核芯+两准粒子模型中热核148—158Sm的比热容及其相变

应用微观核芯+两准粒子模型制备偶148—158Sm同位素的零温度能谱, 其基态带、β带、γ带和部分高自旋态能谱值与最新实验结果符合得较好; 采用正则系综理论, 计算出核的有限温度比热容.基于比热容峰是相变信号，给出了统一描述核发生热激发模式相变、从核超流相到正常相相变和核形状相变的可能性.讨论了两准粒子顺排态能量和指认, 以及核形状的热稳定性.     

The dynamical temperature and the standard map

Numerical experiments with the standard map at high values of the stochasticity parameter reveal the existence of simple analytical relations connecting the volume and the dynamical temperature of the chaotic component of the phase space.     

Stereochemical studies, 73. Saturated heterocycles, 60

N-Substituted-2-carboxamido-1-cycloalkanols were cyclized with 1,1-carbonyldiimidazole to synthesizecis- andtrans-N-alkyl-,N-aralkyl- andN-aryl-2,4-dioxo tri- and tetramethyleneperhydro-1,3-oxazines. The structures of the compounds and theircis ortrans ring anellation were confirmed by IR,¹H- and¹³C-NMR spectroscopy, and thecis andtrans pairs of isomers were compared to establish the predominant conformation of the flexiblecis isomers. It was found that—similarly to the 1,3-oxazin-2- and -4-ones studied earlier—the O-endo conformers are preferred, in which the 1-oxygen atom isaxial to the alicyclic ring; this is independent of the number of ring atoms in the alicycle, and of the presence of an oxazinedione ring, even though this is more flexible that the ring of oxazinones.

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Synthese und Konformation voncis undtrans 2-substituierten kondensierten 1,3-Oxazin-2,4-dionen

Zusammenfassung cis- undtrans-N-Alkyl-,N-Aralkyl- undN-Aryl-2,4-dioxo-, tri- und tetramethylen-perhydro-1,3-oxazine wurden aus 2-Carboxamido-1-cycloalkanolen und 1,1-Carbonyldiimidazol dargestellt. Mit Hilfe der IR,¹H- und¹³C-NMR Spektroskopie wurden die Struktur, diecis- odertrans-Annellierung der Ringe und die bevorzugte Konformation der flexiblencis-Isomeren im Vergleich zumcis-trans Isomerenpaar nachgewiesen. Ähnlich zu den früher untersuchten 1,3-Oxazine-2- und -4-onen ist hier ebenfalls das O-endo Konformere bevorzugt; in diesem ist der Sauerstoffaxial angeordnet, und zwar unabhängig von der Zahl der alicyklischen Ringatome und dem flexibleren Oxazindionring.

     

Triaxial interaction effect in the structure of ^148-158Sm

The structures of ^148-158Sm are studied in the frame of the interacting boson model. Attention is given to the triaxial interaction, and it is found that the triaxial interaction plays an important role in the detailed structure of this isotopic chain. The potential surfaces of these nuclei are also studied and the shapes of them are analysed. And it is found that though the triaxial interaction plays an important role in these nuclei, there are no stable triaxial shapes in the low-lying structures of these nuclei.     

A generalization of a conjecture due to Erd?s, Jacobson and Lehel

An r-graph is a loopless undirected graph in which no two vertices are joined by more than r edges. An r-complete graph on m+1 vertices, denoted by , is an r-graph on m+1 vertices in which each pair of vertices is joined by exactly r edges. A non-increasing sequence π=(d₁,d₂,…,d_n) of nonnegative integers is r-graphic if it is realizable by an r-graph on n vertices. Let be the smallest even integer such that each n-term r-graphic sequence with term sum of at least is realizable by an r-graph containing as a subgraph. In this paper, we determine the value of for sufficiently large n, which generalizes a conjecture due to Erd?s, Jacobson and Lehel.