The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Interaction of rac-[Cu(diimine)<SUB>3</SUB>]<SUP>2+</SUP> and rac-[Zn(diimine)<SUB>3</SUB>]<SUP>2+</SUP> complexes with CT DNA: effect of fluxional Cu(II) geometry on DNA binding, ligand-promoted exciton coupling and prominent DNA cleavage

The complexes [Cu(phen)3](ClO4)21, [Cu(5,6-dmp)3](ClO4)22, [Cu(dpq)3](ClO4)23, [Zn(phen)3](ClO4)24, [Zn(5,6-dmp)3](ClO4)25 and [Zn(dpq)3](ClO4)26, where phen = 1,10-phenanthroline, 5,6-dmp = 5,6-dimethyl-1,10-phenanthroline and dpq = dipyrido[3,2-d:2',3'-f]quinoxaline, have been isolated, characterized and their interaction with calf thymus DNA studied by using a host of physical methods. The X-ray crystal structures of rac-[Cu(5,6-dmp)3](ClO4)22 and rac-[Zn(5,6-dmp)3](ClO4)25 have been determined. While 2 possesses a regular elongated octahedral coordination geometry (REO), 5 possesses a distorted octahedral geometry. Absorption spectral titrations of the Cu(II) complexes with CT DNA reveal that the red-shift (12 nm) and DNA binding affinity of 3 (Kb, 7.5 &#215; 104 M-1) are higher than those of 1 (red-shift, 6 nm; Kb, 9.6 &#215; 103 M-1) indicating that the partial insertion of the extended phen ring of dpq ligand in between the DNA base pairs is deeper than that of phen ring. Also, 2 with a fluxional Cu(II) geometry interacts with DNA (Kb, 3.8 &#215; 104 M-1) more strongly than 1 suggesting that the hydrophobic forces of interaction of 5,6 methyl groups on the phen ring is more pronounced than the partial intercalation of phen ring in the latter with a static geometry. The DNA binding affinity of 1 is lower than that of its Zn(II) analogue 4, and, interestingly, the DNA binding affinity of 2 with a fluxional geometry is higher than that of its Zn(II) analogue 5 with a spherical geometry. It is remarkable that upon binding to DNA 3 shows an increase in viscosity higher than that the intercalator EthBr does, which is consistent with the above DNA binding affinities. The CD spectra show only one induced CD band on the characteristic positive band of CT DNA upon interaction with the phen (1,4) and dpq (3,6) complexes. In contrast, the 5,6-dmp complexes 2 and 5 bound to CT DNA show exciton-coupled biphasic CD signals with 2 showing CD signals more intense than 5. The &#916;-enantiomer of rac-[Cu(5,6-dmp)3]2+2 binds specifically to the right-handed B-form of CT DNA at lower ionic strength (0.05 M NaCl) while the &#916;-enantiomer binds specifically to the left-handed Z-form of CT DNA generated by treating the B-form with 5 M NaCl. The complex 2 is stabilized in the higher oxidation state of Cu(II) more than its phen analogue 1 upon binding to DNA suggesting the involvement of electrostatic forces in DNA interaction of the former. In contrast, 3 bound to DNA is stabilized as Cu(I) rather than the Cu(II) oxidation state due to partial intercalative interaction of the dpq ligand. The efficiencies of the complexes to oxidatively cleave pUC19 DNA vary in the order, 3 &gt; 1 &#187; 2 with 3 effecting 100% cleavage even at 10 &#181;M complex concentration. However, interestingly, this order is reversed when the DNA cleavage is performed using H2O2 as an activator and the highest cleavage efficiency of 2 is ascribed to its electrostatic interaction with the exterior phosphates of DNA

Induction of cell death by ternary copper(II) complexes of L-tyrosine and diimines: role of coligands on DNA binding and cleavage and anticancer activity

The mononuclear mixed ligand copper(II) complexes of the type [Cu(l-tyr)(diimine)](ClO4), where tyr is l-tyrosine and diimine is 2,2'-bipyridine (bpy) (1), 1,10-phenanthroline (phen) (2), 5,6-dimethyl-1,10-phenanthroline (5,6-dmp) (3), and dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) (4), have been isolated and characterized by analytical and spectral methods. In the X-ray crystal structure 3 Cu(II) possesses a distorted square pyramidal coordination geometry with the two nitrogen atoms of 5,6-dmp ligand and the amine nitrogen and carboxylate oxygen atoms of l-tyrosine located at the equatorial sites and the coordinated water molecule present in the apical position. The electronic absorption and electron paramagnetic resonance (EPR) spectral parameters reveal that the complexes retain their square-based geometries even in solution. All of the complexes display a ligand field band in the visible region (600-700 nm) in Tris-HCl/NaCl buffer (5:50 mM) at pH 7.2 and also axial EPR spectra in acetonitrile at 77 K with g &gt; g&#8869; indicating a dx2-y2 ground state. The g and A values of 2.230 and (170-180) &#215; 10-4 cm-1, respectively, conform to a square-based CuN3O coordination chromophore, which is consistent with the X-ray crystal structure of 3. The interaction of the complexes with calf thymus DNA (CT DNA) has been explored by using physical methods to propose modes of DNA binding of the complexes. Absorption (Kb) and emission spectral studies and viscosity measurements indicate that 4 interacts with DNA more strongly than all of the other complexes through partial intercalation of the extended planar ring of dpq with DNA base stack. Interestingly, complex 3 exhibits a DNA binding affinity that is higher than that of 2, which suggests the involvement of 5,6-dimethyl groups on the phen ring in hydrophobic interaction with DNA surface. In contrast with the increase in relative viscosities of DNA bound to 2-4, the viscosity of DNA bound to 1 decreases, indicating the shortening of the DNA chain length by means of the formation of kinks or bends. All complexes exhibit effective DNA (pUC19 DNA) cleavage at 100 &#956; M complex concentrations, and the order of DNA cleavage ability varies as 3 &gt; 2 &gt; 4 &gt; 1. Interestingly, 3 exhibits a DNA cleavage rate constant that is higher than that of the other complexes only at 100 &#956; M concentration, whereas 4 exhibits the highest cleavage rate constant at 80 &#181;M complex concentration. The oxidative DNA cleavage follows the order 4 &gt; 3 &gt; 2 &gt; 1. Mechanistic studies reveal that the DNA cleavage pathway involves hydroxyl radicals. Interestingly, only 4 displays efficient photonuclease activity upon irradiation with 365 nm light, which occurs through double-strand DNA breaks involving hydroxyl radicals. Furthermore, cytotoxicity studies on the nonsmall lung cancer (H-460) cell line show that the IC50 values of 2-4 are more or less equal to cisplatin for the same cell line, indicating that they have the potential to act as very effective anticancer drugs in a time-dependent manner. The study of cytological changes reveals the higher induction of apoptosis and mitotic catastrophe for 4 and 3, respectively. The alkaline single-cell gel electrophoresis (comet assay), DNA laddering, and AO/EB and Hoechst 33258 staining assays have also been employed in finding the extent of DNA damage. Flow cytometry analysis shows an increase in the percentage of cells with apoptotic morphological features in the sub-G0/G1 phase for 4, whereas it shows mitotic catastrophe for 3

Reaction of PerR with Molecular Oxygen May Assist H2O2 Sensing in Anaerobes.

International audiencePerR is the peroxide resistance regulator found in several pathogenic bacteria and governs their resistance to peroxide stress by inducing enzymes that destroy peroxides. However, it has recently been implicated as a key component of the aerotolerance in several facultative or strict anaerobes, including the highly pathogenic Staphylococcus aureus. By combining (18)O labeling studies to ESI- and MALDI-TOF MS detection and EMSA experiments, we demonstrate that the active form of PerR reacts with dioxygen, which leads ultimately to disruption of the PerR/DNA complex and is thus physiologically meaningful. Moreover, we show that the presence of O2 assists PerR sensing of H2O2, another feature likely to be important for anaerobic organisms. These results allow one to envisage different scenarios for the response of anaerobes to air exposure

Single glutamate to aspartate mutation makes ferric uptake regulator (Fur) as sensitive to H2O2 as peroxide resistance regulator (PerR).

International audienc

Mixed Ligand Copper(II) Complexes of <i>N</i>,<i>N</i>-Bis(benzimidazol-2-ylmethyl)amine (BBA) with Diimine Co-Ligands: Efficient Chemical Nuclease and Protease Activities and Cytotoxicity

A series of mononuclear mixed ligand copper­(II) complexes [Cu­(bba)­(diimine)]­(ClO₄)₂ <b>1</b>–<b>4</b>, where bba is <i>N</i>,<i>N</i>-bis­(benzimidazol-2-ylmethyl)­amine and diimine is 2,2′-bipyridine (bpy) (<b>1</b>), 1,10-phenanthroline (phen) (<b>2</b>), 5,6-dimethyl-1,10-phenanthroline (5,6-dmp) (<b>3</b>), or dipyrido­[3,2-<i>d</i>:2′,3′-<i>f</i>]­quinoxaline (dpq) (<b>4</b>), have been isolated and characterized by analytical and spectral methods. The coordination geometry around copper­(II) in <b>2</b> is described as square pyramidal with the two benzimidazole nitrogen atoms of the primary ligand bba and the two nitrogen atoms of phen (<b>2</b>) co-ligand constituting the equatorial plane and the amine nitrogen atom of bba occupying the apical position. In contrast, the two benzimidazole nitrogen atoms and the amine nitrogen atom of bba ligand and one of the two nitrogen atoms of 5,6-dmp constitute the equatorial plane of the trigonal bipyramidal distorted square based pyramidal (TBDSBP) coordination geometry of <b>3</b> with the other nitrogen atom of 5,6-dmp occupying the apical position. The structures of <b>1</b>–<b>4</b> have been optimized by using the density functional theory (DFT) method at the B3LYP/6-31G­(d,p) level. Absorption spectral titrations with Calf Thymus (CT) DNA reveal that the intrinsic DNA binding affinity of the complexes depends upon the diimine co-ligand, dpq (<b>4</b>) > 5,6-dmp (<b>3</b>) > phen (<b>2</b>) > bpy (<b>1</b>). The DNA binding affinity of <b>4</b> is higher than <b>2</b> revealing that the π-stacking interaction of the dpq ring in between the DNA base pairs with the two bzim moieties of the bba ligand stacked along the DNA surface is more intimate than that of phen. The complex <b>3</b> is bound to DNA more strongly than <b>1</b> and <b>2</b> through strong hydrophobic interaction of the methyl groups on 5,6-positions of the phen ring in the DNA grooves. The extent of the decrease in relative emission intensities of DNA-bound ethidium bromide (EB) upon adding the complexes parallels the trend in DNA binding affinities. The large enhancement in relative viscosity of DNA upon binding to <b>3</b> and <b>4</b> supports the DNA binding modes proposed. Interestingly, the 5,6-dmp complex <b>3</b> is selective in exhibiting a positive induced CD band (ICD) upon binding to DNA suggesting that it induces a B to A conformational change. In contrast, <b>2</b> and <b>4</b> show induced CD responses indicating their involvement in strong DNA binding. Interestingly, only the dpq complex <b>4</b>, which displays the strongest DNA binding affinity and is efficient in cleaving DNA in the absence of an activator with a rate constant of 5.8 ± 0.1 h^–1, which is higher than the uncatalyzed rate of DNA cleavage. All the complexes exhibit oxidative DNA cleavage ability, which varies as <b>4</b> > <b>2</b> > <b>3</b> > <b>1</b> (ascorbic acid) and <b>3</b> > <b>2</b> > <b>4</b> > <b>1</b> (H₂O₂). Also, the complexes cleave the protein bovine serum albumin in the presence of H₂O₂ as an activator with the cleavage ability varying in the order <b>3</b> > <b>4</b> > <b>2</b> > <b>1</b>. The highest efficiency of <b>3</b> to cleave both DNA and protein in the presence of H₂O₂ is consistent with its strong hydrophobic interaction with the biopolymers. The IC₅₀ values of <b>1</b>–<b>4</b> against cervical cancer cell lines (SiHa) are almost equal to that of cisplatin, indicating that they have the potential to act as effective anticancer drugs in a time-dependent manner. The morphological assessment data obtained by using acridine orange/ethidium bromide (AO/EB) and Hoechst 33258 staining reveal that <b>3</b> induces apoptosis much more effectively than the other complexes. Also, the alkaline single-cell gel electrophoresis study (comet assay) suggests that the same complex induces DNA fragmentation more efficiently than others

Mixed Ligand Copper(II) Complexes of <i>N</i>,<i>N</i>-Bis(benzimidazol-2-ylmethyl)amine (BBA) with Diimine Co-Ligands: Efficient Chemical Nuclease and Protease Activities and Cytotoxicity

A series of mononuclear mixed ligand copper­(II) complexes [Cu­(bba)­(diimine)]­(ClO₄)₂ <b>1</b>–<b>4</b>, where bba is <i>N</i>,<i>N</i>-bis­(benzimidazol-2-ylmethyl)­amine and diimine is 2,2′-bipyridine (bpy) (<b>1</b>), 1,10-phenanthroline (phen) (<b>2</b>), 5,6-dimethyl-1,10-phenanthroline (5,6-dmp) (<b>3</b>), or dipyrido­[3,2-<i>d</i>:2′,3′-<i>f</i>]­quinoxaline (dpq) (<b>4</b>), have been isolated and characterized by analytical and spectral methods. The coordination geometry around copper­(II) in <b>2</b> is described as square pyramidal with the two benzimidazole nitrogen atoms of the primary ligand bba and the two nitrogen atoms of phen (<b>2</b>) co-ligand constituting the equatorial plane and the amine nitrogen atom of bba occupying the apical position. In contrast, the two benzimidazole nitrogen atoms and the amine nitrogen atom of bba ligand and one of the two nitrogen atoms of 5,6-dmp constitute the equatorial plane of the trigonal bipyramidal distorted square based pyramidal (TBDSBP) coordination geometry of <b>3</b> with the other nitrogen atom of 5,6-dmp occupying the apical position. The structures of <b>1</b>–<b>4</b> have been optimized by using the density functional theory (DFT) method at the B3LYP/6-31G­(d,p) level. Absorption spectral titrations with Calf Thymus (CT) DNA reveal that the intrinsic DNA binding affinity of the complexes depends upon the diimine co-ligand, dpq (<b>4</b>) > 5,6-dmp (<b>3</b>) > phen (<b>2</b>) > bpy (<b>1</b>). The DNA binding affinity of <b>4</b> is higher than <b>2</b> revealing that the π-stacking interaction of the dpq ring in between the DNA base pairs with the two bzim moieties of the bba ligand stacked along the DNA surface is more intimate than that of phen. The complex <b>3</b> is bound to DNA more strongly than <b>1</b> and <b>2</b> through strong hydrophobic interaction of the methyl groups on 5,6-positions of the phen ring in the DNA grooves. The extent of the decrease in relative emission intensities of DNA-bound ethidium bromide (EB) upon adding the complexes parallels the trend in DNA binding affinities. The large enhancement in relative viscosity of DNA upon binding to <b>3</b> and <b>4</b> supports the DNA binding modes proposed. Interestingly, the 5,6-dmp complex <b>3</b> is selective in exhibiting a positive induced CD band (ICD) upon binding to DNA suggesting that it induces a B to A conformational change. In contrast, <b>2</b> and <b>4</b> show induced CD responses indicating their involvement in strong DNA binding. Interestingly, only the dpq complex <b>4</b>, which displays the strongest DNA binding affinity and is efficient in cleaving DNA in the absence of an activator with a rate constant of 5.8 ± 0.1 h^–1, which is higher than the uncatalyzed rate of DNA cleavage. All the complexes exhibit oxidative DNA cleavage ability, which varies as <b>4</b> > <b>2</b> > <b>3</b> > <b>1</b> (ascorbic acid) and <b>3</b> > <b>2</b> > <b>4</b> > <b>1</b> (H₂O₂). Also, the complexes cleave the protein bovine serum albumin in the presence of H₂O₂ as an activator with the cleavage ability varying in the order <b>3</b> > <b>4</b> > <b>2</b> > <b>1</b>. The highest efficiency of <b>3</b> to cleave both DNA and protein in the presence of H₂O₂ is consistent with its strong hydrophobic interaction with the biopolymers. The IC₅₀ values of <b>1</b>–<b>4</b> against cervical cancer cell lines (SiHa) are almost equal to that of cisplatin, indicating that they have the potential to act as effective anticancer drugs in a time-dependent manner. The morphological assessment data obtained by using acridine orange/ethidium bromide (AO/EB) and Hoechst 33258 staining reveal that <b>3</b> induces apoptosis much more effectively than the other complexes. Also, the alkaline single-cell gel electrophoresis study (comet assay) suggests that the same complex induces DNA fragmentation more efficiently than others