Watch and wait for Rectal Cancer: A 9 year Experience.

Background: Neoadjuvant long course chemoradiotherapy has become the standard treatment for locally advanced rectal cancer. It can reduce tumour bulk, downstage, reduce the risk of local recurrence, and increase the possibility of clear resection margins. The aim of our study is to evaluate all patients over a 9 year period who underwent neoadjuvant chemoradiotherapy for rectal cancer and entered our watch and wait programme. Methods: Data were analysed from a prospective database for all patients diagnosed with rectal cancer over a 9 year period (2011-2019 inclusive). Findings: Over a 9 year period, 532 patients were treated for rectal cancer, with 180 patients receiving long course chemoradiotherapy. 61 (11%) patients entered a watch and programme as they had a complete clinical and radiological response following chemoradiotherapy. Within this programme, 40 patients (65%) remain disease free over the follow-up period (mean 38 months); 12 (20%) patients had regrowth and proceeded to surgery; and 9 (15%) proceeded to palliation due to being unfit for surgery or had distant metastatic disease. Overall (all cause) mortality was 18% during follow-up period in the watch and wait group. Conclusions: Neoadjuvant long course chemoradiotherapy is the standard treatment for locally advanced rectal cancer. 34% of our patient group who received long course chemoradiotherapy entered a watch and wait programme with the majority avoiding major rectal surgery.

A sequential cyclization/π-extension strategy for modular construction of nanographenes enabled by stannole cycloadditions.

The synthesis of polycyclic aromatic hydrocarbons (PAHs) and related nanographenes requires the selective and efficient fusion of multiple aromatic rings. For this purpose, the Diels-Alder cycloaddition has proven especially useful; however, this approach currently faces significant limitations, including the lack of versatile strategies to access annulated dienes, the instability of the most commonly used dienes, and difficulties with aromatization of the [4 + 2] adduct. In this report we address these limitations via the marriage of two powerful cycloaddition strategies. First, a formal Cp2Zr-mediated [2 + 2 + 1] cycloaddition is used to generate a stannole-annulated PAH. Secondly, the stannoles are employed as diene components in a [4 + 2] cycloaddition/aromatization cascade with an aryne, enabling π-extension to afford a larger PAH. This discovery of stannoles as highly reactive - yet stable for handling - diene equivalents, and the development of a modular strategy for their synthesis, should significantly extend the structural scope of PAHs accessible by a [4 + 2] cycloaddition approach.

Copper(III) Metallacyclopentadienes via Zirconocene Transfer and Reductive Elimination to an Isolable Phenanthrocyclobutadiene.

Despite the widespread use of copper catalysis for the formation of C-C bonds, debate about the mechanism persists. Reductive elimination from Cu(III) is often invoked as a key step, yet examples of its direct observation from isolable complexes remain limited to only a few examples. Here, we demonstrate that incorporation of bulky mesityl (Mes) groups into the α-positions of a phenanthrene-appended zirconacyclopentadiene, Cp2Zr(2,5-Mes2-phenanthro[9,10]C4), enables efficient oxidative transmetalation to the corresponding, formal Cu(III) metallacyclopentadiene dimer. The dimer was quantitatively converted to a structurally analogous anionic monomer [nBu4N]{Cl2Cu(2,5-Mes2-phenanthro[9,10]C4)} upon treatment with [nBu4N][Cl]. Both metallacycles undergo quantitative reductive elimination upon heating to generate phenanthrocyclobutadiene and a Cu(I) species. Due to the steric protection provided by the mesityl groups, this cyclobutadiene was isolated and thoroughly characterized to reveal antiaromaticity comparable to that of free cyclobutadiene, which imbues it with a small highest occupied molecular orbital-lowest unoccupied molecular orbital energy gap of 1.85 eV and accessible reduced and oxidized electronic states.

Running a mentalization-based treatment (MBT) programme within a public community adult mental health service setting: a feasibility study.

OBJECTIVES: This article aimed to address the feasibility of mentalization-based treatment (MBT) for patients with personality disorder in a non-specialist setting. The development and implementation of an MBT Programme is described. METHODS: A multidisciplinary Consult Group met to plan the implementation of the programme. Participants attended a psychoeducation group (MBT Introductory Group), then weekly individual and group therapy. Fourteen participants started the full programme with eight completing at least 9 months, complete data are available for five participants who completed 27 months (first cohort) and 21 months (second cohort). Data include quantitative measures and qualitative questionnaires/interviews. All had a diagnosis of personality dysfunction with co-morbid disorder including anxiety/depressive disorder, post-traumatic stress disorder and eating disorder. RESULTS: Data on five participants revealed reductions in global level of distress, improvements in psychological well-being, less interpersonal difficulties and better work and social functioning. Qualitative data from feedback questionnaires (n = 18) and in-depth interview (n = 2) are discussed under the themes of mentalizing, treatment feedback/outcomes and group factors. Therapist reflections on the process identify the challenges involved in implementing a specialist psychotherapy programme within a general service and learning points from this are discussed. CONCLUSIONS: MBT is an acceptable treatment for patients with personality dysfunction. Prior to the implementation of a programme, factors at the therapist, team and organizational level, as well as the wider context, need to be examined. This is to ensure that conditions are in place for proper adherence to the model to achieve the positive outcomes demonstrated in the RCT studies.

ATR FTIR Study of the Interaction of TiO2 Nanoparticle Films with ß-Lactoglobulin and Bile Salts.

The technique of in situ particle film attenuated total reflection Fourier transform infrared spectroscopy (ATR FTIR) has been used to probe the adsorption and coadsorption (sequential) of a common food protein (ß-lactoglobulin, BLG) and two representative bile salts (taurocholic acid and glycocholic acid, abbreviated as TCA and GCA) onto the surface of titanium dioxide (TiO2) nanoparticles. Evaluating of binding interactions between commonly used (historically now, in some countries) food additives and food components, as well as the body's own digestion chemicals, is a critical step in understanding the role of colloidal phenomena in digestion and bioavailability. TCA is found to adsorb onto TiO2 but without any significant ability to be retained when it is not present in the aqueous phase. GCA is also found to adsorb via two distinct binding mechanisms, with one type of adsorbed species being resistant to removal. BLG adsorbs, is irreversibly bound, and has altered conformation when adsorbed at pH 2 (stomach conditions) to the conformation when adsorbed at pH 6.5 (small intestine conditions). This altered conformation is not interface-dependent and is mirrored in the solution spectra of BLG. Sequential coadsorption studies indicate that TCA and GCA adsorb onto TiO2 nanoparticle surfaces and display similar degrees of reversibility and binding in the presence or absence of preadsorbed BLG.

Direct metal-carbon bonding in symmetric bis(C-H) agostic nickel(i) complexes.

Agostic interactions are examples of σ-type interactions, typically resulting from interactions between C-H σ-bonds with empty transition metal d orbitals. Such interactions often reflect the first step in transition metal-catalysed C-H activation processes and thus are of critical importance in understanding and controlling σ bond activation chemistries. Herein, we report on the unusual electronic structure of linear electron-rich d9 Ni(i) complexes with symmetric bis(C-H) agostic interactions. A combination of Ni K edge and L edge XAS with supporting TD-DFT/DFT calculations reveals an unconventional covalent agostic interaction with limited contributions from the valence Ni 3d orbitals. The agostic interaction is driven via the empty Ni 4p orbitals. The surprisingly strong Ni 4p-derived agostic interaction is dominated by σ contributions with minor π contributions. The resulting ligand-metal donation occurs directly along the C-Ni bond axis, reflecting a novel mode of bis-agostic bonding.

Role of Phosphine Sterics in Strained Aminophosphine Chelate Formation.

The preparation of four-membered aminophosphine (PN) chelates from common metal precursors has largely evaded realization because of the ring strain associated with these species. We report a straightforward approach to the synthesis of such PN metallacycles using simple α-PN ligands analogous to the popular class of small-bite-angle diphosphinomethane ligands. It is demonstrated that bulky phosphine substituents are important to the formation of these chelates.

Understanding Ni(II)-Mediated C(sp3)-H Activation: Tertiary Ureas as Model Substrates.

We report a mechanistic study of C(sp3)-H bond activation mediated by nickel. Cyclometalated Ni(II) ureate [(PEt3)Ni(κ3- C,N,N-(CH2)N(Cy)(CO)N((N)-quinolin-8-yl))] was synthesized and isolated from the urea precursor, (Me)(Cy)N(CO)N(H)(quinolin-8-yl), via C(sp3)-H activation. We investigated the effects of solvents and base additives on the rate of C-H activation. Kinetic isotope effect experiments showed that C-H activation is rate determining. Through deuterium labeling and protonation studies, we also showed that C-H activation can be reversible. We extended this reaction to a range of ureas with primary and secondary C(sp3)-H bonds, which activate readily to form analogous nickelated products. Finally, we showed that carboxylate additives assist with both ligand dissociation and initial N-H bond activation, consistent with a concerted metalation-deprotonation mechanism.

Dynamic wetting of imidazolium-based ionic liquids on gold and glass.

Many of the applications of ionic liquids rely on their bulk properties or their solvation abilities. However, it is their interactions with solid surfaces that underpin many of their potential applications in advanced technologies. Whether it is as lubricants for wind turbines or as electrolytes in supercapacitors, there are many areas where ionic liquids can provide an improvement in performance relative to more commonplace liquids. However, there are some barriers to their implementation in such applications. Foremost of these is the lack of systematic studies of their interactions with solid surfaces as well as neglecting the effect of the absorbed water on wetting. The present study explores the dynamic wetting of three ionic liquids (with a different length of hydrocarbon chain in the cation) on gold and glass substrates, both of which are relevant for nano- and micromechanical machine applications, under well-controlled environmental conditions. The form of data capture (Wilhelmy plate) allows for a direct analysis using analytical expressions for the two dominant approaches for dynamic wetting: the hydrodynamic and molecular kinetic models. All ionic liquids yield data that are described best by the molecular kinetic model. Substrate-ionic liquid and water-ionic liquid interactions contribute to the mechanisms involved in the wetting process.

A room temperature cyanation of (hetero)aromatic chlorides by an air stable nickel(ii) XantPhos precatalyst and Zn(CN)2.

A methodology for the synthesis of (hetero)aromatic nitriles from aryl chlorides at room temperature has been developed. This methodology uses an air and moisture stable nickel(ii) XantPhos precatalyst and Zn(CN)2 as the cyanide (CN-) source.

Oxidation State Dependent Coordination Modes: Accessing an Amidate-Supported Nickel(I) δ-bis(C-H) Agostic Complex.

Amidate-supported two- and three-coordinate NiI complexes were synthesized by reduction of the corresponding NiII precursors. A dramatic change in binding mode is observed upon reduction from NiII to NiI . The NiI derivatives include an unprecedented NiI bis(C-H) agostic complex and a two-coordinate NiI complex.

Arylative Desulfonation of Diarylmethyl Phenyl Sulfone with Arenes Catalyzed by Scandium Triflate.

A scandium-triflate-catalyzed arylative desulfonation of diarylmethyl phenyl sulfones with arenes and heteroarenes was established. A variety of both sulfone and arene substrates were reacted to afford symmetric and nonsymmetric triarylmethanes in good yields. Further transformations of the resulting triarylmethanes and application to the concise synthesis of a bactericidal agent analogue were also demonstrated.

An in vitro investigation of the cardiovascular effects of the 5-HT(4) receptor selective agonists, velusetrag and TD-8954.

The 5-HT(4) receptor agonists, and gastrointestinal (GI) prokinetic agents, cisapride and tegaserod, lack selectivity for the 5-HT(4) receptor. Cisapride is a potent human ether-à-go-go-related gene (hERG) potassium channel inhibitor while cisapride and tegaserod have significant affinity for 5-HT(1) and 5-HT(2) receptor subtypes. Marketing of both compounds was discontinued due to cardiovascular concerns (cardiac arrhythmias with cisapride and ischemic events with tegaserod). The reported association of tegaserod with ischemia has been postulated to involve coronary artery constriction or augmentation of platelet aggregation. This in vitro study investigated the effects of two of the new generation of highly selective 5-HT(4) receptor agonists, velusetrag and TD-8954, on canine, porcine and human coronary artery tone, human platelet aggregation and hERG potassium channel conductance. No significant off-target actions of velusetrag or TD-8954 were identified in these, and prior, studies. While cisapride inhibited potently the hERG channel currents, tegaserod failed to affect platelet aggregation, and had only a small contractile effect on the canine coronary artery at high concentrations. Tegaserod inhibited the 5-HT-induced contractile response in the porcine coronary artery. New generation 5-HT(4) receptor agonists hold promise for the treatment of patients suffering from GI motility disorders with a reduced cardiovascular risk.

Clinical trial: the efficacy and tolerability of velusetrag, a selective 5-HT4 agonist with high intrinsic activity, in chronic idiopathic constipation - a 4-week, randomized, double-blind, placebo-controlled, dose-response study.

BACKGROUND: Velusetrag is an orally active 5-HT(4) receptor agonist of potential benefit in treating chronic idiopathic constipation. AIM: To evaluate the efficacy, safety and tolerability of velusetrag in chronic idiopathic constipation. METHODS: After a 2-week baseline period, patients [<3 spontaneous bowel movements (SBM)/week] received placebo or velusetrag (15, 30 or 50 mg) daily for 4 weeks in a randomized, double-blind design, followed by a 1-week follow-up period. The primary endpoint was the change from baseline in weekly SBM frequency averaged over the 4-week treatment period. RESULTS: Patients receiving velusetrag (15, 30 and 50 mg) achieved statistically and clinically significant increases in weekly SBM frequency relative to those receiving placebo. Mean increases were 3.6, 3.3 and 3.5 SBM/week respectively, compared with 1.4 SBM/week for placebo (P < 0.0001). Statistically significant increases in the weekly frequency of complete SBM (CSBM) were also reported (mean increases of 2.3, 1.8 and 2.3 for 15, 30 and 50 mg velusetrag respectively, compared with 0.6 for placebo). Common adverse events associated with velusetrag were diarrhoea, headache, nausea and vomiting, generally occurring during the initial days of dosing. CONCLUSION: Velusetrag was efficacious and well tolerated in patients with chronic idiopathic constipation (ClinicalTrials.gov identifier NCT00391820).

Clinical phenotype of cystic fibrosis patients with the G551D mutation.

BACKGROUND: Data on whether the phenotype of cystic fibrosis (CF) patients with compound heterozygocity for G551D (Gly551Asp) differs from patients with F508del (Phe508del) homozygous mutations is divergent. AIM: We hypothesized that CF patients with the G551D mutation would have less severe disease than F508del homozygotes. DESIGN: We compared the clinical phenotype of adult patients with a G551D mutation with adult patients homozygous for F508del and those with the missense mutation R117H (Arg117His). Compound heterozygotes for the G551D and R117H were analysed separately. METHODS: Data were collected for 101 adult CF patients. Group 1-4 represents in order F508del homozygote patients (n = 61), those with the G551D mutation and a more severe mutation (n = 13), those with R117H mutation and a more severe mutation (n = 23) and also those compound for both the R117H and G551D mutations (n = 4). RESULTS: Our findings have shown that adult patients with the G551D mutation and a second severe mutation have a milder clinical phenotype than F508del homozygous adult patients. Higher FEV(1) and body mass index and less impaired glucose tolerance was demonstrated in the patients with G551D and R117H compared to F508del homozygotes. There was a reduced yearly rate of decline of FEV(1) (P < 0.05), infection with Pseudomonas aeruginosa along with reduced burden of care. Compound heterozygosity for G551D and R117H mutations was associated with normal spirometry, body mass index, no chronic infection and no symptoms. CONCLUSION: Mutations on different chromosomes are not independent of each other for the overall impact on the amount of functional CFTR. This study suggests that patients with the G551D mutation and a second severe mutation have a milder clinical phenotype than F508del homozygous patients, but the phenotype is not as mild as patients with the R117H mutation.

The in vivo gastrointestinal activity of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity.

The in vivo preclinical pharmacodynamic profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity, was compared to that of the clinically studied gastrointestinal pro-kinetic agents, tegaserod, cisapride and mosapride. The activity of TD-5108 was evaluated in guinea pig colonic transit, rat oesophageal relaxation and dog gastrointestinal smooth muscle contractility models. Subcutaneous administration of TD-5108, tegaserod, cisapride and mosapride increased guinea pig colonic transit (rank order of potencies: TD-5108 > tegaserod > cisapride > mosapride). Following intravenous and intraduodenal dosing, TD-5108, tegaserod, cisapride and mosapride produced dose-dependent relaxation of the rat oesophagus. On a molar basis, TD-5108 was approximately twofold less potent than tegaserod following intravenous dosing but 6- or 86-fold more potent than cisapride or mosapride, respectively, and 9- or 18-fold more potent than tegaserod or cisapride, respectively, after intraduodenal administration. Orally dosed TD-5108 increased the contractility of the canine antrum, duodenum and jejunum with higher potency than tegaserod. The selective 5-HT(4) receptor agonist, TD-5108, demonstrates robust in vivo activity in the guinea pig, rat and dog gastrointestinal tracts.

The in vitro pharmacological profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity.

The in vitro pharmacological profile of TD-5108, a novel, selective 5-HT(4) receptor agonist, was compared to that of clinically efficacious gastroprokinetic 5-HT(4) receptor agonists. TD-5108 produced an elevation of cyclic adenosine monophosphate in human embryonic kidney 293 cells expressing the human recombinant 5-HT(4(c)) (h5-HT(4(c))) receptor (pEC(50) = 8.3) and 5-HT(4) receptor-mediated relaxation of the rat esophagus (pEC(50) = 7.9) and contraction of the guinea pig colon (pEC(50) = 7.9). In all in vitro assays, TD-5108 was a high intrinsic activity agonist, unlike tegaserod, mosapride, and cisapride which, in the majority of test systems, had lower intrinsic activity. TD-5108 had high affinity (pK (i) = 7.7) and selectivity (> or =25-fold) for h5-HT(4(c)) receptors over other biogenic amine receptors. TD-5108 was >500-fold selective over other 5-HT receptors (including h5-HT(2B) and h5-HT(3A)) and, at 3 microM, had no effect on human ether-à-go-go-related gene K+ channels. In conclusion, TD-5108 is a selective 5-HT(4) receptor agonist in vitro. The high intrinsic activity and preferential binding of TD-5108 to 5-HT4 over other 5-HT receptors may result in an improved clinical profile for the treatment of gastrointestinal disorders of reduced motility.

Serotonin pharmacology in the gastrointestinal tract: a review.

Serotonin (5-hydroxytryptamine or 5-HT) plays a critical physiological role in the regulation of gastrointestinal (GI) function. 5-HT dysfunction may also be involved in the pathophysiology of a number of functional GI disorders, such as chronic constipation, irritable bowel syndrome and functional dyspepsia. This article describes the role of 5-HT in the enteric nervous system (ENS) of the mammalian GI tract and the receptors with which it interacts. Existing serotonergic therapies that have proven effective in the treatment of GI functional disorders and the potential of drugs currently in development are also highlighted. Advances in our understanding of the physiological and pathophysiological roles of 5-HT in the ENS and the identification of selective receptor ligands bodes well for the future development of more efficacious therapies for patients with functional GI disorders.

In situ ATR FTIR studies of SO4 adsorption on goethite in the presence of copper ions.

Despite the existence of many single ion sorption studies on iron and aluminum oxides, fewer studies have been reported that describe cosorption reactions. In this work, we present an in situ ATR FTIR study of synergistic adsorption of sulfate (SO4) and copper (Cu) on goethite, which is representative of the minerals and ions present in mine wastes, acid sulfate soils, and other industrial and agricultural settings. Sulfate adsorption was studied as a function of varying pH, and as a function of increasing concentration in the absence and presence of Cu. The presence of Cu ions in solution had a complex effect on the ability of SO4 ions to be retained on the goethite surface with increasing pH, with complete desorption occurring near pH 7 and 9 in the absence and presence of Cu, respectively. In addition, Cu ions altered the balance of inner vs outer sphere adsorbed SO4. The solid phase partitioning of SO4 at pH 3 and pH 5 was elevated by the presence of Cu; in both cases Cu increased the affinity of SO4 for the goethite surface. Complementary ex situ sorption edge studies of Cu on goethite in the absence and presence of SO4 revealed that the Cu adsorption edge shifted to lower pH (6.3 --> 5.6) in the presence of SO4, consistent with a decrease of the electrostatic repulsion between the goethite surface and adsorbing Cu. Based on the ATR FTIR and bulk sorption data we surmise that the cosorption products of SO4 and Cu at the goethite-water interface were not in the nature of ternary complexes under the conditions studied here. This information is critical for the evaluation of the onset of surface precipitates of copper-hydroxy sulfates as a function of pH and solution concentration.