X‐ray crystallographic evidence shows that nucleophilic substitution reactions of two different types of cyclophosphazene derivatives with relatively rigid nine‐membered ansa rings leads to the first ...demonstration of retention of configuration in these molecular systems.
X‐ray crystallography provides evidence of retention of configuration in nucleophilic substitution reactions of two different types of cyclophosphazene derivatives (see example) containing nine‐membered ansa rings that are relatively rigid, which suggests that this mechanism may be less rare than considered previously.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Poor nutrition is associated with a loss of residual renal function and inferior clinical outcome in peritoneal dialysis (PD) patients. The value of increasing the PD dose in these individuals is ...unclear. An open, prospective, longitudinal, "intention to treat" study was performed on a whole PD population. All patients treated during an 18-month recruitment period underwent nutritional assessment and were defined as malnourished if they had a subjective global assessment (SGA) of B or C and were 5% or more below their desirable body weight. These patients received an intended dialysis dose increase of 25% and were reassessed after six months. Dialysis was not increased in the remaining patients, unless dictated by uremic symptoms. Forty-eight of 153 patients were malnourished by the previously mentioned criteria. When compared with well-nourished PD patients, they had evidence of declining nutrition over the previous 12 months, as judged by a loss in body weight and mid-arm circumference (MAC), a reduced creatinine appearance, a reduced appetite for protein and calories, and low plasma albumin. They had been on treatment longer and had less residual renal function, resulting in significantly poorer solute clearances. Their peritoneal membrane function, plasma bicarbonate, comorbid, Karnofsky, Hospital Anxiety and Depression (HAD) scores were not different. Following intervention, their peritoneal Kt/Vurea was increased by 22.5%, and their total Kt/Vurea by 18%, because of a continued loss of residual function. There was also an increase in dialysis-derived calories. Weight and MAC stabilized after an initial deterioration, and creatinine appearance increased. There was no increase in protein intake, as judged by dietetic interview or protein nitrogen appearance. Oral calorie intake improved, as did plasma albumin after an initial decline. Both of these improvements were correlated with the achieved increase in Kt/Vurea. Objective measures of improvement (plasma albumin and protein nitrogen appearance) were significant in those patients without comorbid disease. These results support the existing evidence that malnutrition is acquired on PD in those patients who lose residual renal function. It is feasible to increase the dialysis dose in these individuals without a detrimental effect, and there is evidence of a modest benefit in patients without comorbidity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The siloxane-based linker hexakis(4-carboxyphenyl)disiloxane (L-H6) has been used in the construction of four 3D MOFs via treatment with Cd2+, Ce3+, Y3+ and Zn2+ salts. The underlying nets in these ...MOFs have been evaluated through deconstruction of their crystal structures and subsequent topological analysis.
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Four metal–organic frameworks containing hexatopic connectors have been prepared and structurally characterised: Cd3(L)(DMA)2(H2O)2 (IMP-28), Ce2(L)(DMF)2(H2O)2 (IMP-29), Y2(L)(DMF)2(H2O)2 (IMP-30), and Zn2(L-H2)(4,4′-bipy)2 (IMP-31). All the MOFs have been constructed using the hybrid inorganic–organic siloxane linker hexakis(4-carboxyphenyl)disiloxane (L-H6). In each case, discrete metal-based nodes are cross-linked by the octahedrally disposed connector to afford 3D polymeric structures. The underlying nets in these MOFs have been evaluated through deconstruction of their crystal structures and subsequent topological analysis. Examples of MOFs built from hexatopic linkers, and especially those with octahedral predispositions such as in L, remain scarce and the topologies ascribed to some of these MOFs are unique.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Icodextrin has been shown in randomized controlled trials to benefit fluid management in peritoneal dialysis (PD). We describe international icodextrin prescription practices and their relationship ...to clinical outcomes.
We analyzed data from the prospective, international PDOPPS, from Australia/New Zealand, Canada, Japan, the United Kingdom, and the United States. Membrane function and 24-hour ultrafiltration according to icodextrin and glucose prescription was determined at baseline. Using an instrumental variable approach, Cox regression, stratified by country, was used to determine any association of icodextrin use to death and permanent transfer to hemodialysis (HDT), adjusted for demographics, comorbidities, serum albumin, urine volume, transplant waitlist status, PD modality, center size, and study phase.
Icodextrin was prescribed in 1986 (35%) of 5617 patients, >43% of patients in all countries, except in the United States, where it was only used in 17% and associated with a far greater use of hypertonic glucose. Patients on icodextrin had more coronary artery disease and diabetes, longer dialysis vintage, lower residual kidney function, faster peritoneal solute transfer rates, and lower ultrafiltration capacity. Prescriptions with or without icodextrin achieved equivalent ultrafiltration (median 750 ml/d interquartile range 300-1345 ml/d versus 765 ml/d 251-1345 ml/d). Icodextrin use was not associated with mortality (HR=1.03; 95% CI, 0.72 to 1.48) or HDT (HR 1.2; 95% CI, 0.92 to 1.57).
There are large national and center differences in icodextrin prescription, with the United States using significantly less. Icodextrin was associated with hypertonic glucose avoidance but equivalent ultrafiltration, which may affect any potential survival advantage or HDT.
Abstract
DNA-dependent kinase (DNA-PK) is a nuclear serine/threonine protein kinase complex that is a key component of the non-homologous end joining (NHEJ) process. DNA-PK plays an important role in ...the cellular response to DNA damage through the detection and repair of DNA double strand breaks (DSB). Cancer therapies such as ionising radiation (IR) or topoisomerase II inhibitors (doxorubicin) generate DSB which can be repaired by homologous recombination (HR) or non-homologous end-joining (NHEJ). It can therefore be hypothesised a DNA-PK inhibitor would potentiate the activity of these agents. We have developed a highly potent and selective inhibitor of DNA-PK, AZD7648, which inhibits IR-induced DNA-PK S2056 auto phosphoryalation with an IC50 = 92 nM in A549 non-small cell lung cancer (NSCLC) cells. AZD7648 is a potent radiosensitiser where treatment in combination with IR led to a concentration-dependent reduction of the colony survival capacity of A549 and H1299 NSCLC cells (DEF37 at 100 nM = 1.7 and 2.5, respectively). In A549 cells, AZD7648 (≥1 µM) in combination with 2Gy IR for 48 hours led to a significant accumulation of cells arrested in the G2/M of the cell cycle, a 4-fold increase in micronuclei formation, and 3-fold induction of γH2AX, pATM S1981 and 53BP1 foci formation compared with IR alone. AZD7648 was also found to combine synergistically with doxorubicin in a panel of ovarian and triple negative breast cancer (TNBC) cell lines in cell growth inhibition assays when applying the Loewe additivity model (synergy scores 4 - 35). In vivo the combination of AZD7648 with IR (5x 2Gy) induced tumour regression in H1299 and A549 NSCLC xenografts in a dose-dependent manner (84 and 11% regression respectively), while monotherapy treatment only achieved tumour growth inhibition. In these two models the increased activation by IR of three primary DNA-PK pharmacodynamic markers, pDNAPK (S2056), pRPA32 (S4/8) and γH2AX, was inhibited by AZD7648 treatment (70-90% inhibition 2 h after IR + AZD7648). Similarly, liposomal doxorubicin (2.5 mg/kg weekly) in combination with AZD7648 (37.5 mg/kg bid) induced tumour regressions in the BT474c ER+ breast cancer xenograft model and in a TNBC PDX model (63% and 33% regression respectively), while monotherapy treatments only achieved tumour growth inhibition. These data confirm that DNA-PK inhibition with AZD7648 enhances the efficacy of a range of DSB inducing agents in vitro and in vivo, providing a clear rationale for its clinical investigation.
Citation Format: Jacqueline H. Fok, Antonio Ramos-Montoya, Neil James, Mercedes Vazquez-Chantada, Valeria Follia, Ankur Karmokar, Anna Staniszewska, Lenka Oplustil O’Connor, Emma Dean, Simon J. Hollingsworth, Barry R. Davies, Elaine B. Cadogan. AZD7648, a potent and selective inhibitor of DNA-PK, potentiates the activity of ionising radiation and doxorubicin in vitro and causes tumour regression in xenograft models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3512.
Abstract
DNA-dependent kinase (DNA-PK) is a nuclear serine/threonine protein kinase complex that is a key component of the non-homologous end joining (NHEJ) process. DNA-PK plays an important role in ...the cellular response to DNA damage through the detection and repair of DNA double strand breaks (DSB) and is a critical component of the DNA Damage Response (DDR). DSB can be induced by a range of agents, including chemotherapy, radiation or Poly ADP Ribose Polymerase (PARP) inhibitors such as olaparib, and thus a DNA-PK inhibitor is likely to sensitize to these agents. DNA-PK inhibitors may also be effective as monotherapy in tumors with high endogenous levels of DNA damage resulting from defects in other DNA repair pathways. We have developed a highly potent and selective inhibitor of DNA-PK, AZD7648 (pDNA-PK IC50 in A549 cells = 92 nM). AZD7648 shows broad growth inhibitory activity across a panel of 244 cancer cell lines (GI50 1.3 - 30 µM). Consistent with known synthetic lethal interactions with DNA-PK, AZD7648 shows a 10-13-fold greater growth inhibitory effect in FaDu head and neck and A549 non-small cell lung cancer cell lines with ATM knocked out (KO) by zinc finger nuclease or CRISPR respectively compared to their isogenic wild-type counterparts (WT). This growth inhibition is associated with increased levels of DNA damage as measured by micronuclei formation detected using high-content immunofluorescence (2-fold increase vs DMSO at 2 µM AZD7648). Moreover, a 6-fold increase in chromosomal breaks are detected in the ATM KO cells using metaphase spread analysis (mean breaks/cell: FaDu ATM KO = 1.7, ATM WT = 0.28) In vivo, monotherapy treatment with AZD7648 (75-100 mg/kg bid) inhibited tumor growth in a panel of 14 PDX and 2 xenograft models, derived from breast, lung, ovarian and head and neck cancers. This included models with and without loss of ATM. Treatment with AZD7648 resulted in dose-dependent inhibition of the phosphorylation of DNA-PK (S2056), RPA32 (S4/8) and nuclear γH2AX in FaDu ATM KO xenografts, where AZD7648 75mg/kg inhibited γH2AX and phosphorylation of DNA-PK (S2056) and RPA32 (S4/8) by 71, 98 and 95% respectively at 2 h after dosing. These data confirm that DNAPK inhibition using AZD7648 has potent pharmacodynamic and monotherapy anti-tumor activity in a range of pre-clinical models. This includes, but is not restricted to, models with engineered and endogenous loss of ATM.
Citation Format: Elaine B. Cadogan, Jacqueline H. Fok, Antonio Ramos-Montoya, Neil James, Valeria Follia, Mercedes Vazquez-Chantada, Paul Winjhoven, Lenka Oplustil O’Connor, Ankur Karmokar, Anna Staniszewska, Emma Dean, Simon J. Hollingsworth, Barry Davies. AZD7648: A potent and selective inhibitor of DNA-PK with pharmacodynamic and monotherapy anti-tumor activity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3505.
Abstract
DNA-dependent kinase (DNA-PK) is a nuclear serine/threonine protein kinase complex and a key component of the non-homologous end joining (NHEJ) process. DNA-PK plays an important role in the ...cellular response to DNA damage through the detection and repair of double strand breaks (DSB). DSB can be induced by a range of agents, including chemotherapy and radiation. The PARP inhibitor olaparib has also been shown to induce DSB as a consequence of trapping PARP proteins at sites of damaged DNA. Therefore, we hypothesised that DNA-PK inhibitors may combine therapeutically with PARP inhibitors. AZD7648 is a highly potent and selective inhibitor of DNA-PK (pDNA-PK cell IC50 = 92 nM) The combination treatment of AZD7648 with olaparib for 10 - 12 days in vitro leads to at least 20% greater cell growth inhibition compared with either agents as monotherapies in a panel of cell lines with deficiencies in the ATM pathway (e.g. cells lacking ATM protein or where ATM substrates are not phosphorylated after exposure to DSB inducing agents). This effect is also seen in isogenic ATM knock-out (KO) FaDu head and neck and A549 non-small cell lung cancer cell lines. At concentrations of AZD7648 (0.6 - 2 µM) and olaparib (1 µM) that have monotherapy activity in the ATM KO cells but not in their wild-type counterparts (WT), the combination treatment enhanced the G2/M cell cycle arrest caused by olaparib and led to greater levels of micronuclei formation as detected using high-content immunofluorescece assays (mean per cell: FaDu WT = 0.1, FaDu ATM KO = 0.4). This was associated with a larger quantity of chromosomal aberrations in the ATM KO versus WT cells following combination treatment detected by metaphase spread analysis (mean per cell: FaDu ATM KO = 5.5, FaDu WT = 1.2). The same phenotype was observed in A549 ATM KO versus WT cell lines. In vivo, continuous dosing of AZD7648 (75 mg/kg bid) in combination with olaparib (100 mg/kg qd) inhibited the growth of FaDu WT tumours by ~60%. However, in the FaDu ATM KO tumours complete regressions were seen after 70 days of dosing and no re-growth was detected up to 220 days later. Additionally, in PDX models of breast, lung, ovarian and head and neck cancer this combination showed tumour growth inhibition (50-100%) in 13 models and regression in 5 models, only one of these five models being ATM pathway deficient. These data confirm that DNA-PK inhibition using AZD7648 enhances the efficacy of olaparib in vitro and in vivo, providing a clear rationale for its clinical investigation.
Citation Format: Antonio Ramos-Montoya, Jacqueline H. Fok, Neil James, Valeria Follia, Mercedes Vazquez-Chantada, Paul Wijnhoven, Lenka Oplustil O’Connor, Ankur Karmokar, Anna Staniszewska, Emma Dean, Simon J. Hollingsworth, Barry Davies, Elaine B. Cadogan. AZD7648, a potent and selective inhibitor of DNA-PK, potentiates activity of the PARP inhibitor olaparib resulting in sustained anti-tumour activity in xenograft and PDX models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3506.
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