Cisplatin Radiosensitization of DNA Irradiated with 2–20 eV Electrons: Role of Transient Anions

Platinum chemotherapeutic agents, such as cisplatin (<i>cis</i>-diamminedichloroplatinum­(II)), can act as radiosensitizers when bound covalently to nuclear DNA in cancer cells. This radiosensitization is largely due to an increase in DNA damage induced by low-energy secondary electrons, produced in large quantities by high-energy radiation. We report the yields of single- and double-strand breaks (SSB and DSB) and interduplex cross-links (CL) induced by electrons of 1.6–19.6 eV (i.e., the yield functions) incident on 5 monolayer (ML) films of cisplatin–DNA complexes. These yield functions are compared with those previously recorded with 5 ML films of unmodified plasmid DNA. Binding of five cisplatin molecules to plasmid DNA (3197 base pairs) enhances SSB, DSB, and CL by factors varying, from 1.2 to 2.8, 1.4 to 3.5, and 1.2 to 2.7, respectively, depending on electron energy. All yield functions exhibit structures around 5 and 10 eV that can be attributed to enhancement of bond scission, via the initial formation of core-excited resonances associated with π → π* transitions of the bases. This increase in damage is interpreted as arising from a modification of the parameters of the corresponding transient anions already present in nonmodified DNA, particularly those influencing molecular dissociation. Two additional resonances, specific to cisplatin-modified DNA, are formed at 13.6 and 17.6 eV in the yield function of SSB. Furthermore, cisplatin binding causes the induction of DSB by electrons of 1.6–3.6 eV, i.e., in an energy region where a DSB cannot be produced by a single electron in pure DNA. Breaking two bonds with a subexcitation-energy electron is tentatively explained by a charge delocalization mechanism, where a single electron occupies simultaneously two σ* bonds linking the Pt atom to guanine bases on opposite strands

Screw penetration rate in the three fracture classification systems.

<p>Screw penetration rate in the three fracture classification systems.</p

Copper-Catalyzed Oxidative Cross-Dehydrogenative Coupling/Oxidative Cycloaddition: Synthesis of 4‑Acyl-1,2,3-Triazoles

A copper-catalyzed three-component reaction of methyl ketones, organic azides, and various one-carbon (C1) donors was developed that provides 4-acyl-1,2,3-triazoles in moderate to good yields. While DMF, DMA, TMEDA, or DMSO can serve as the C1 donor, best yields were obtained using DMF. The transformation is proposed to proceed via an oxidative C–H/C–H cross-dehydrogenative coupling followed by an oxidative 1,3-dipolar cycloaddition

Trauma-series x-rays of a 75-year-old woman at the follow-up of three months after surgery, the black arrow pointed at the screw penetrating the joint while it was missed on the true glenoid anteroposterior and transscapular lateral radiographs.

<p>Trauma-series x-rays of a 75-year-old woman at the follow-up of three months after surgery, the black arrow pointed at the screw penetrating the joint while it was missed on the true glenoid anteroposterior and transscapular lateral radiographs.</p

Correlation between classification and secondary screw penetration in proximal humeral fractures

<div><p>Objectives</p><p>In this study, we investigated the correlation between fracture classification and secondary screw penetration.</p><p>Methods</p><p>We retrospectively identified 189 patients with displaced proximal humeral fractures treated by ORIF at our hospital between June 2006 and June 2013. All fractures were classified radiographically before surgery and follow-up for least 2 years after surgery was recommended. At each follow-up, radiographs were taken in three orthogonal views to evaluate secondary screw penetration.</p><p>Results</p><p>The study population consisted of 189 patients. Of these, 70 were male and 119 female, with a mean age of 59.1 years; the mean follow-up time was 28.5 months. Secondary screw penetration occurred in 26 patients. The risk of developing secondary screw penetration was 11.3-fold higher in four-part fractures than two-part fractures (<i>P</i> < 0.05), 8.6-fold higher for type C fractures than type A fractures (<i>P</i> < 0.05) and 11.0-fold higher for medial hinge disruption group than intact medial hinge group fractures (<i>P</i> < 0.05). However there was no difference between three-part fractures and two-part fractures (<i>P</i> = 0.374), and between type B and type A fractures (<i>P</i> = 0.195). Age, gender, time to surgery and the number of screw in humeral head had no influence on the secondary screw penetration rate (<i>P</i> > 0.05).</p><p>Conclusions</p><p>Patients with four-part fractures, type C fractures and medial hinges disruption are vulnerable to secondary screw penetration. This allows additional precautions to be instituted and measures to be taken as needed.</p></div

Allylic C–S Bond Construction through Metal-Free Direct Nitroalkene Sulfonation

A metal-free, open-flask protocol was developed for the preparation of allylic sulfones through direct condensation of sodium arylsulfinates and β,β-disubstituted nitroalkenes. The key step of this process was the Lewis base-promoted equilibrium between nitroalkenes and allylic nitro compounds. Through this process, the readily available conjugated nitroalkenes can be easily converted into allylic nitro compounds, which contain more reactive CC bonds toward the sulfonyl radical addition. As a result, allylic sulfones were prepared in excellent yields with a broad substrate scope under mild conditions

Synthesis of [1,2,3]Triazolo[5,1-<b><i>a</i></b>]isoquinoline Derivatives via a Selective Cascade Cyclization Sequence of 1,2-bis(Phenylethynyl)benzene Derivatives

<div><p></p><p>A direct, concise, synthetic method for the generation of [1,2,3]triazolo[5,1-<i>a</i>]isoquinoline derivatives, using a selective cascade cyclization of unsymmetrical substituted 1,2-bis(phenylethynyl)benzene derivatives with NaN₃, has been developed. The reaction gave different substituted [1,2,3]triazolo[5,1-<i>a</i>]isoquinolines in moderate to good yields. It was found that the substituents on the alkynes were important for the selectivities of the cascade cyclization sequences.</p></div

Molecular efficacy of radio- and chemotherapy sequences from direct DNA damage measurements

<p><b>Purpose:</b> To investigate the molecular aspects of the synergy between ionizing radiation and platinum (Pt) chemotherapeutic agents in cancer treatment with chemoradiation therapy (CRT) by measuring damages induced by low-energy electrons (LEE) to DNA bound to cisplatin. LEE are produced abundantly by any type of ionizing radiation and cisplatin represents a typical Pt-chemotherapeutic agents.</p> <p><b>Materials and methods:</b> Our strategy involves two parallel administrations of cisplatin and irradiation with a 4.6 and 9.6 eV electron fluence of 1.1 × 10¹²: (1) LEE bombardment of supercoiled DNA and its subsequent reaction with cisplatin; (2) the reaction of DNA with cisplatin followed by LEE irradiation. The damage yields for the loss of supercoiled (LS), single-strand breaks (SSB) and double-strand breaks (DSB) were obtained from gel electrophoresis analysis. Base modifications were revealed by treating the samples with <i>Escherichia coli</i> base excision repair endonuclease (Nth and Fpg).</p> <p><b>Results:</b> The yields were deduced from the respective time–response for the reaction of DNA with cisplatin. The results show that binding cisplatin to DNA followed by LEE irradiation, consistently yields more DNA damages than the reverse order. In comparison to non-treated DNA, administration (2) results in an increase of LS and SSB of 1.4–3.3 folds and of DSB by more than an order of magnitude. Furthermore, after enzyme treatment, the yields of DSB rise by factors of 5.3–15.4, indicating a large increase of clustered damages, which should at least partially translate into an increase of lethal damages in cancer cells during the CRT.</p> <p><b>Conclusions:</b> Our results demonstrate that a strong synergy between radiation and cisplatin can only be achieved at the molecular level, if the drug is present at the time of irradiation. Furthermore, this work confirms the LEE mechanism previously proposed to explain the synergy between radiation and Pt drugs in CRT. It involves chemical sensitization of DNA prior to irradiation, to facilitate strand breaks and clustered damages induced by the highly reactive LEE.</p

Copper-Catalyzed [3 + 2] Cycloaddition/Oxidation Reactions between Nitro-olefins and Organic Azides: Highly Regioselective Synthesis of NO₂‑Substituted 1,2,3-Triazoles

A new copper-catalyzed [3 + 2] cycloaddition/oxidation reaction of nitro-olefins with organic azides has been developed to afford 1,4­(-NO₂),5-trisubstituted 1,2,3-triazoles. This reaction sequence has a broad substrate scope and affords NO₂-substituted 1,2,3-triazoles with high regioselectivities and in good to excellent yields. The involved oxidative process overcomes the elimination of HNO₂ for general cycloaddition of nitro-olefins with organic azides, which shows a high atom economy and potential applications

Copper-Catalyzed Cross-Dehydrogenative <i>N</i>²‑Coupling of <i>NH</i>-1,2,3-Triazoles with <i>N</i>,<i>N</i> -Dialkylamides: <i>N</i>‑Amidoalkylation of <i>NH</i>-1,2,3-Triazoles

An efficient copper-catalyzed C–N bond formation by N–H/C–H cross-dehydrogenative coupling (CDC) between <i>NH</i>-1,2,3-triazoles and <i>N</i>,<i>N</i>-dialkylamides has been developed. The method provided <i>N</i>-amidoalkylated 1,2,3-triazoles with moderate to high yields, and the reactions showed high <i>N</i>²-selectivities when 4,5-disubstituted <i>NH</i>-1,2,3-triazoles served as the substrates