A Study on Auto-Catalysis and Product Inhibition: A Nucleophilic Aromatic Substitution Reaction Catalysed within the Cavity of an Octanuclear Coordination Cage.

The ability of an octanuclear cubic coordination cage to catalyse a nucleophilic aromatic substitution reaction on a cavity-bound guest was studied with 2,4-dinitrofluorobenzene (DNFB) as the guest/substrate. It was found that DNFB undergoes a catalysed reaction with hydroxide ions within the cavity of the cubic cage (in aqueous buffer solution, pH 8.6). The rate enhancement of kcat/kuncat was determined to be 22, with cavity binding of the guest being required for catalysis to occur. The product, 2,4-dinitrophenolate (DNP), remained bound within the cavity due to electrostatic stabilisation and exerts two apparently contradictory effects: it initially auto-catalyses the reaction when present at low concentrations, but at higher concentrations inhibits catalysis when a pair of DNP guests block the cavity. When encapsulated, the UV/Vis absorption spectrum of DNP is red-shifted when compared to the spectrum of free DNP in aqueous solution. Further investigations using other aromatic guests determined that a similar red-shift on cavity binding also occurred for 4-nitrophenolate (4NP) at pH 8.6. The red-shift was used to determine the stoichiometry of guest binding of DNP and 4NP within the cage cavity, which was confirmed by structural analysis with X-ray crystallography; and was also used to perform catalytic kinetic studies in the solution-state.

MOF matrix isolation: cooperative conformational mobility enables reliable single crystal transformations.

Obtaining structural information for highly reactive metal-based species can provide valuable insight into important chemical transformations or catalytic processes. Trapping these metal-based species within the cavities of porous crystalline hosts, such as metal-organic frameworks (MOFs), can stabilise them, allowing detailed structural elucidation by single crystal X-ray diffraction. Previously, we have used a bespoke flexible MOF, [Mn3L2L'] (MnMOF-1, where L = bis-(4-carboxyphenyl-3,5-dimethylpyrazolyl)methane and L = L', but L' has a vacant N,N'-chelation site), which has a chelating site capable of post-synthetically binding metal ions, to study organometallic transformations and fundamental isomerisation processes. This manuscript will report the underlying conformational flexibility of the framework, demonstrate the solvent dependency of post-synthetic metalation, and show that the structural flexibility of the linker site and framework are critical to controlling and achieving high levels of metal loading (and therefore site occupancy) during chemical transformations. From these results, a set of design principles for linker-based "matrix isolation" and structure determination in MOFs are derived.

Characterisation of two self-sufficient CYP102 family monooxygenases from Ktedonobacter racemifer DSM44963 which have new fatty acid alcohol product profiles.

BACKGROUND: Two self-sufficient CYP102 family encoding genes (Krac_0936 and Krac_9955) from the bacterium Ktedonobacter racemifer DSM44963, which possesses one of the largest bacterial genomes, have been identified. METHODS: Phylogenetic analysis of both the encoded cytochrome P450 enzymes, Krac0936 and Krac9955. Both enzymes were produced and their turnovers with fatty acid substrates assessed in vitro and using a whole-cell oxidation system. RESULTS: Krac0936 hydroxylated straight chain, saturated fatty acids predominantly at the ω-1 and ω-2 positions using NADPH as the cofactor. Krac0936 was less active towards shorter unsaturated fatty acids but longer unsaturated acids were efficiently oxidised. cis,cis-9,12-Octadecadienoic and pentadecanoic acids were the most active substrates tested with Krac0936. Unusually Krac9955 showed very low levels of NAD(P)H oxidation activity though coupling of the reducing equivalents to product formation was high. The product distribution of tridecanoic, tetradecanoic and pentadecanoic acid oxidation by Krac9955 favoured oxidation at the ω-4, ω-5 and ω-6 positions, respectively. CONCLUSION: Krac0936 and Krac9955 are self-sufficient P450 monooxygenases. Krac0936 has a preference for pentadecanoic acid over other straight chain fatty acids and showed little or no activity with dodecanoic or octadecanoic acids. Krac9955 preferably oxidised shorter fatty acids compared to Krac0936 with tridecanoic having the highest levels of product formation. Unlike Krac0936 and P450Bm3, Krac9995 showed lower activities with unsaturated fatty acids. GENERAL SIGNIFICANCE: In this study of two of the CYP enzymes from K. racemifer we have shown that this bacterium from the Chloroflexi phylum contains genes which encode new proteins with novel activity.

Panitumumab added to docetaxel, cisplatin and fluoropyrimidine in oesophagogastric cancer: ATTAX3 phase II trial.

BACKGROUND: This randomised phase II study evaluated the efficacy and safety of panitumumab added to docetaxel-based chemotherapy in advanced oesophagogastric cancer. METHODS: Patients with metastatic or locally recurrent cancer of the oesophagus, oesophagogastric junction or stomach received docetaxel and a fluoropyrimidine with or without panitumumab for 8 cycles or until progression. The primary end point was response rate (RECIST1.1). We planned to enrol 100 patients, with 50% expected response rate for combination therapy. RESULTS: A total of 77 patients were enrolled. A safety alert from the REAL3 trial prompted a review of data that found no evidence of adverse outcomes associated with panitumumab but questionable efficacy, and new enrolment was ceased. Enrolled patients were treated according to protocol. Response rates were 49% (95% CI 34-64%) in the chemotherapy arm and 58% (95% CI 42-72%) in the combination arm. Common grade 3 and 4 toxicities included infection, anorexia, vomiting, diarrhoea and fatigue. At 23.7 months of median follow-up, median progression-free survival was 6.9 months vs 6.0 months and median overall survival was 11.7 months vs 10.0 months in the chemotherapy arm and the combination arm, respectively. CONCLUSIONS: Adding panitumumab to docetaxel-based chemotherapy for advanced oesophagogastric cancer did not improve efficacy and increased toxicities.

Studying manganese carbonyl photochemistry in a permanently porous metal-organic framework.

Mn(diimine)(CO)3X (X = halide) complexes are critical components of chromophores, photo- and electrocatalysts, and photoactive CO-releasing molecules (photoCORMs). While these entities have been incorporated into metal-organic frameworks (MOFs), a detailed understanding of the photochemical and chemical processes that occur in a permanently porous support is lacking. Here we site-isolate and study the photochemistry of a Mn(diimine)(CO)3Br moiety anchored within a permanently porous MOF support, allowing for not only the photo-liberation of CO from the metal but also its escape from the MOF crystals. In addition, the high crystallinity and structural flexibility of the MOF allows crystallographic snapshots of the photolysis products to be obtained. We report these photo-crystallographic studies in the presence of coordinating solvents, THF and acetonitrile, showing the changing coordination environment of the Mn species as CO loss proceeds. Using time resolved experiments, we report complementary spectroscopic studies of the photolysis chemistry and characterize the final photolysis product as a possible Mn(ii) entity. These studies inform the chemistry that occurs in MOF-based photoCORMs and where these moieties are employed as catalysts.

The preservation of sarin and O,O'-diisopropyl fluorophosphate inside coordination cage hosts.

The host-guest chemistry of O,O'-diisopropyl fluorophosphate (DFP), a phosphonofluoridate G-series chemical warfare agent simulant, was investigated in the presence of a number of octanuclear cubic coordination cage hosts. The aim was to demonstrate cage-catalysed hydrolysis of DFP at near neutral pH: however, two octanuclear coordination cages, HPEG (containing water-solubilising PEG groups) and HW (containing water-solubilising hydroxymethyl groups), were actually found to increase the lifetime of DFP in aqueous buffer solution (pH 8.7). Crystallographic analysis of DFP with a structurally related host cage revealed that DFP binds to windows in the cage surface, not in the internal cavity. The phosphorus-fluorine bond is directed into the cavity rather than towards the external environment, with the cage/DFP association protecting DFP from hydrolysis. Initial studies with the chemical warfare agent (CWA) sarin (GB) with HPEG cage in a buffered solution also showed a drastically reduced rate of hydrolysis for sarin when bound in the host cage. The ability of these cages to inhibit hydrolysis of these P-F bond containing organophosphorus guests, by encapsulation, may have applications in forensic sample preservation and analysis.

Isolating reactive metal-based species in Metal-Organic Frameworks - viable strategies and opportunities.

Structural insight into reactive species can be achieved via strategies such as matrix isolation in frozen glasses, whereby species are kinetically trapped, or by confinement within the cavities of host molecules. More recently, Metal-Organic Frameworks (MOFs) have been used as molecular scaffolds to isolate reactive metal-based species within their ordered pore networks. These studies have uncovered new reactivity, allowed observation of novel metal-based complexes and clusters, and elucidated the nature of metal-centred reactions responsible for catalysis. This perspective considers strategies by which metal species can be introduced into MOFs and highlights some of the advantages and limitations of each approach. Furthermore, the growing body of work whereby reactive species can be isolated and structurally characterised within a MOF matrix will be reviewed, including discussion of salient examples and the provision of useful guidelines for the design of new systems. Novel approaches that facilitate detailed structural analysis of reactive chemical moieties are of considerable interest as the knowledge garnered underpins our understanding of reactivity and thus guides the synthesis of materials with unprecedented functionality.

Probiotics in the United States.

Probiotics are live microbial products that have a defined health benefit. Scientific research has established that there are validated indications for the use of some probiotics available in the United States; however, in many cases, they are often used for conditions for which no benefit has been established. This article will review the uses of probiotics in the United States, as well as the current state of regulatory issues surrounding probiotics. Although the use and scientific understanding of probiotics are rapidly increasing, it is evident that there is a need to clarify the regulatory issues, which, at present, are unclear and subject to misinterpretation. In addition to efficacy, safety issues must be considered in determining when and how probiotics are to be used.

Barriers to a healthy lifestyle for three- to four-year-old children of Australian-born and overseas-born mothers with post-gestational diabetes: An Australian qualitative study.

Children of mothers affected by gestational diabetes mellitus (GDM) are at higher risk of long-term cardio-metabolic diseases. We explore the diet and physical activity knowledge and practices of Australian-born and overseas-born mothers with GDM history, for their three- to four-year-old children following antenatal health promotion education at a tertiary hospital. We conducted face-to-face, semi-structured interviews with 8 Australian-born and 15 overseas-born mothers with a history of GDM. Findings indicated that mothers of both groups were unaware of the increased health risks of their GDM for their children and could not recall receiving specific dietary or physical activity advice aimed at future child health. Their understanding of the diet and physical activity recommendations was inconsistent. Mothers of both groups expressed concern about the lack of reiteration of child health promotion messages following childbirth, particularly at postnatal follow-up visits. Diet and physical activity of the children of overseas-born mothers were adversely affected by inadequate maternal understanding of the recommendations due to language barriers, and child weight, healthy eating, and physical activity patterns derived from their home countries. We recommend enhanced health education for women with GDM on the future child health risks and their reduction by healthy lifestyle choices. This needs to be culturally relevant and reiterated after pregnancy.

nab-Paclitaxel plus gemcitabine in metastatic pancreatic adenocarcinoma: Australian subset analyses of the phase III MPACT trial.

AIM: The phase III MPACT trial (N = 861) demonstrated superior overall survival (OS) with first-line nab-paclitaxel plus gemcitabine versus gemcitabine alone (median, 8.7 months vs 6.6 months; hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.62-0.83; P < 0.001) in patients with metastatic pancreatic cancer. The efficacy benefit of the combination over gemcitabine alone was observed across patient subgroups, including those based on region. This subset analysis was designed to examine the safety and efficacy of nab-paclitaxel plus gemcitabine in patients treated in Australia to understand whether differences in patient population or regional variations in patient care had any impact on clinical outcomes. METHODS: Patients with metastatic pancreatic cancer received first-line nab-paclitaxel plus gemcitabine or gemcitabine alone in the MPACT study; this analysis focused on those treated in Australia. RESULTS: In the Australian cohort, 120 patients were randomized to receive nab-paclitaxel plus gemcitabine (n = 61) or gemcitabine alone (n = 59). Median OS was 9.4 months with nab-paclitaxel plus gemcitabine versus 6.7 months with gemcitabine alone (HR, 0.64; 95% CI, 0.44-0.94; P = 0.022). Progression-free survival (median, 5.5 months vs 3.6 months; HR, 0.65; 95% CI, 0.42-1.00; P = 0.049) and the overall response rate (23% vs 2%; P < 0.001) were significantly improved with the combination. No new safety signals were observed. CONCLUSIONS: The results of this subset analysis confirm the efficacy and manageable safety profile of nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic cancer treated in Australia.

Barriers to a healthy lifestyle post gestational-diabetes: An Australian qualitative study.

BACKGROUND: Overseas-born-women from certain ethnicities are at high risk of type-2 diabetes and related metabolic disorders. This study explored the barriers and facilitators to long-term healthy lifestyle recommendations among Australian-born and overseas-born-women who attended health promotion sessions at a tertiary Australian Hospital for gestational diabetes 3-4 years previously. METHOD: Face-to-face semi-structured interviews were conducted. Data were analyzed to identify major themes and the differing experiences of both groups of women. FINDINGS: Women in both groups faced many barriers to improve post-gestational-diabetes lifestyle. Women from both groups recalled healthy lifestyle recommendations for during pregnancy they received at the service, but had difficulty recalling the long-term lifestyle recommendations. Timing of the health information, non-reiteration of lifestyle recommendations, uncoordinated and fragmented health system support after childbirth were barriers faced by all women. Additional barriers for overseas-born women included the cultural competence of the health education material, their cultural preferences for food and physical activities and unsupportive family and partner. Both groups had excellent compliance with the first annual postnatal oral-glucose-tolerance-test. This was attributed to the personal motivation and health professional reminder. Women only reverted to the healthy lifestyles postnatally for weight loss. CONCLUSION: A better understanding of the barriers to healthy lifestyle by women in their everyday lives will assist in the development of culturally appropriate health promotion guidelines and strategies. Constant un-fragmented postnatal engagement by the specialised diabetes clinics and primary health care services is crucial to sustain the healthy lifestyle in the long-term for women with previous gestational-diabetes.

nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial.

BACKGROUND: Positive findings from the phase III MPACT trial led to the regulatory approval of nab-paclitaxel plus gemcitabine as a treatment option for patients with metastatic pancreatic cancer. This report is an update of overall survival (OS) based on longer follow-up. METHODS: Patients (n = 861) with metastatic pancreatic cancer and a Karnofsky performance status of 70 or greater were randomly assigned one to one to receive nab-paclitaxel + gemcitabine or gemcitabine alone. Efficacy data for this post hoc analysis were collected through May 9, 2013. Exploratory analyses of carbohydrate antigen 19-9 (CA19-9) and neutrophil-to-lymphocyte ratio (NLR) were conducted. The primary efficacy endpoint was OS, which was analyzed for all randomly assigned patients by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: The median OS was statistically significantly longer for nab-paclitaxel plus gemcitabine vs gemcitabine alone (8.7 vs 6.6 months, hazard ratio [HR] = 0.72, 95% confidence interval [CI] = 0.62 to 0.83, P < .001). Long-term (>three-year) survivors were identified in the nab-paclitaxel plus gemcitabine arm only (4%). In pooled treatment arm analyses, higher CA19-9 level and NLR at baseline were statistically significantly associated with worse OS. There appeared to be a treatment effect for OS favoring nab-paclitaxel plus gemcitabine over gemcitabine alone in poor-prognosis subgroups defined by these factors (HR = 0.612, P < .001 for CA19-9 level ≥ median and HR = 0.81, P = .079 for NLR > 5). CONCLUSIONS: These data confirm and extend the primary report of OS, supporting the superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone. Subgroup analyses support the relevance of CA 19-9 and NLR as prognostic markers in metastatic pancreatic cancer.

Enteral and parenteral nutrition in the care of patients with short-bowel syndrome.

Short-bowel syndrome is a challenging entity for the gastroenterologist, requiring integration of medical, nutritional, surgical and psychological therapies. Treatment must be based on the patient's age, remaining gastrointestinal anatomy, baseline nutritional status and underlying general health as well as the numerous complications which may arise. This chapter reviews physiological alterations that occur with short-bowel syndrome and how therapies can be tailored to most adequately meet the needs of these patients. Emphasis on early stages of therapy to enhance intestinal adaptation is focused on as management during this time has a significant impact on the long-term outcome of these patients.

New and emerging therapies for short bowel syndrome in children.

This review provides an overview of traditional as well as emerging therapies useful in the management of pediatric short bowel syndrome. Pediatric short bowel syndrome is relatively uncommon; however, when it does occur, it presents a unique challenge to medical care providers. The use of parenteral and enteral nutrition to maximize growth and enhance intestinal adaptation so as to increase absorptive surface area has been the primary focus of therapy. In recent years, the advent of pharmacologic advances, including the use of antibacterial drugs, anti-motility drugs and hormonal therapies, has had a significant impact on this condition. At times, surgery may be indicated for dealing with complications, or providing alternative therapy such as transplantation. With ongoing research, it is likely that improved pharmacologic therapy will be available for enhanced intestinal adaptation, control of gut motility, treatment of small bowel bacterial overgrowth, and treatment of rejection following small intestinal transplantation.

Overview of considerations for the pediatric patient receiving home parenteral and enteral nutrition.

Pediatric home nutrition support is a common practice used to provide children with impaired gastrointestinal function and their caregivers a therapeutic environment for the delivery of needed nutrition for proper growth and development. Specialized teams and equipment are now available to make this a successful experience for all involved. This paper will review items specific to the care of infants and children receiving both enteral and parenteral nutrition.

Probiotic use in children.

Interest in nutritional supplements and functional foods has risen significantly in recent years. Many of the products that are marketed to consumers tout the benefits of probiotics for general good health and for a wide variety of conditions and situations. Although most of these products have been used safely for years, careful analysis of scientific research should be conducted before routinely recommending these products, especially for children. A basic understanding of intestinal flora, properties of probiotics, and clinical research findings is necessary for clinicians to delineate the role of probiotic agents in the pediatric population.