Helicobacter pylori (H pylori) is the main risk factor for gastric cancer (GC). In recent years, many studies have addressed the effects of H pylori itself and of H pylori‐induced chronic ...inflammation on DNA damage. Unrepaired or inappropriately repaired DNA damage is one possible carcinogenic mechanism. We may conclude that H pylori‐induced DNA damage is one of the carcinogenic mechanisms of GC. In this review, we summarize the interactions between H pylori and DNA damage and the effects of H pylori‐induced DNA damage on GC. Then, focusing on oxidative stress, we introduce the application of antioxidants in GC. At the end of this review, we discuss the outlook for further research on H pylori‐induced DNA damage.
The solitons collision in nonplanar (cylindrical and spherical) plasmas consisting of positive ions, two different negative ions, and isothermal electrons is studied. For this purpose, the ...Poincaré–Lighthill–Kuo (PLK) method is used to obtain two-coupled nonplanar Korteweg–de Vries (nKdV) equations. Also, the nonplanar phase shifts are calculated. The physical parameters of two plasma experiments; namely Xe+–F−–SF6− and Ar+–F−–SF6− are used to examine the properties of the localized pulses and their phase shifts after collision. It is found that the present model gives rise to the propagation of positive and negative pulses. The effects of the total negative ions concentration, the density ratio of the second-negative ions, the temperature ratio, and the geometrical effects on the behavior of solitons collisions and their phase shifts are investigated. Furthermore, it is found that the phase shifts in the case of the Ar+–F−–SF6− plasma are much larger than those of the Xe+–F−–SF6− plasma. Also, for fixed plasma parameters, the solitons collision received the largest phase shift in spherical geometry, followed by the cylindrical and planar geometries.
•The nonplanar solitons collisions are investigated.•The PLK technique is used to study the solitons collisions.•The phase shifts of the compressive and rarefactive solitons collisions are studied.•The physical parameters of two plasma environments (e.g., Xe+–F−–SF6− and Ar+–F−–SF6−) are examined on the phase shifts.•The present plasma system supports the positive and negative phase shifts.
Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught ...us about the intricacies of oncogenic RAS signalling that allow us to now get a pharmacological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. Thus far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF-dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase-independent functions in apoptosis, cell cycle progression and cell migration.
Head-on collision between two hydroelastic solitary waves propagating at the surface of an incompressible and ideal fluid covered by a thin ice sheet is analytically studied by means of a singular ...perturbation method. The ice sheet is represented by the Plotnikov-Toland model with the help of the special Cosserat theory of hyperelastic shells and the Kirchhoff-Love plate theory, which yields the nonlinear and conservative expression for the bending forces. The shallow water assumption is taken for the fluid motion with the Boussinesq approximation. The resulting governing equations are solved asymptotically with the aid of the Poincaré-Lighthill-Kuo method, and the solutions up to the third order are explicitly presented. It is observed that solitary waves after collision do not change their shapes and amplitudes. The wave profile is symmetric before collision, and it becomes, after collision, unsymmetric and titled backward in the direction of wave propagation. The wave profile significantly reduces due to greater impacts of elastic plate and surface tension. A graphical comparison is presented with published results, and the graphical comparison between linear and nonlinear elastic plate models is also shown as a special case of our study.
Background
Volasertib induces mitotic arrest and apoptosis by targeting Polo‐like kinases. In this phase I dose‐escalation study, the maximum tolerated dose (MTD), pharmacokinetics (PK), and ...preliminary efficacy of volasertib were determined in pediatric patients.
Methods
Patients aged 2 to <18 years with relapsed/refractory acute leukemia/advanced solid tumors (ST) without available effective treatments were enrolled—cohort C1 (aged 2 to <12 years); cohort C2 (aged 12 to <18 years). The patients received volasertib intravenously (starting dose: 200 mg/m2 body surface area on day 1, every 14 days). The primary endpoint was the pediatric MTD for further development.
Results
Twenty‐two patients received treatment (C1: leukemia, n = 4; ST, n = 8; C2: leukemia, n = 3; ST, n = 7). No dose‐limiting toxicities (DLTs) occurred up to 300 mg/m2 volasertib in C1; two patients in C2, at 250 mg/m2 volasertib, had DLTs in cycle 1, one of which led to death; therefore, the MTD of volasertib in C2 was 200 mg/m2. The most common grade 3/4 adverse events (all patients) were febrile neutropenia, thrombocytopenia, and neutropenia (41% each). Stable disease (SD) was the best objective response (leukemia, n = 5; ST, n = 2); the duration of SD was short in all patients, except in one with an ST. PK profiles were generally comparable across dose groups and were consistent with those in adults.
Conclusion
The pediatric MTD/dose for further development was identified. There were no unexpected safety or PK findings; limited antitumor/antileukemic activity was demonstrated.
The problem of the head-on collision of two ion-acoustic solitary waves (IASWs) is addressed in electronegative plasmas with a nonextensive electron velocity distribution. Our plasma model is ...inspired from the experimental studies of Ichiki et al. (2001). Using the extended Poincare–Lighthill–Kuo (PLK) perturbation method, the phase shifts of the head-on collision are obtained. Analytical and numerical results reveal that the magnitude of the phase shift of the IASWs depends sensitively on the number density ratios μ and υ, the mass ratio σ as well as the nonextensive parameter q. For a given mass ratio σ≃0.27 (Ar+−SF6−), the magnitude of the phase shift increases with an increase of the nonextensive parameter q. An increase of the electron-to-positive ion density ratio μ lowers the phase shift, a trend which is much perceptible for q>1. As σ increases σ≃0.89 (Xe+−SF6−), the phase shift becomes larger.
•Electronegative plasmas having nonextensive electrons.•Head-on collision of two ion-acoustic solitary waves.•Extended Poincare–Lighthill–Kuo (PLK) perturbation method.•Phase shift of the colliding ion-acoustic solitary waves.
Abstract Aims BI 2536 is a selective and potent small-molecule inhibitor of polo-like kinase 1. We performed a multi-centre, multi-tumour phase II trial to investigate the efficacy, safety and ...pharmacokinetics of BI 2536 in five solid tumour types. Patients and methods Patients with advanced head and neck, breast and ovarian cancer, soft tissue sarcoma and melanoma were selected according to protocol-defined general and tumour-specific criteria. They were ⩾18 years old, had a good performance status, adequate bone marrow, renal and liver function, measurable progressive disease and had completed other relevant systemic treatments >4 weeks ago. BI 2536 200–250 mg was given intravenously on day 1 every 3 weeks until intolerance, progression or refusal. The study was based on a Simon two-stage design, with 12 patients entering in stage 1 and additional 25 patients to be entered in case of at least one response in the first stage. The rate of objective responses (RECIST criteria) was chosen as primary end-point. Results Seventy six patients were included, 71 started treatment and received a median number of two cycles (four in ovarian cancer). Frequent grade 3–4 adverse events were neutropaenia (81.6%), thrombocytopaenia (19.7%), febrile neutropaenia (19.7%), anaemia (15.5%) and pain (9.9%). We did not observe confirmed objective responses. All cohorts were closed after the entry of 14–15 eligible non-responding patients. Pharmacokinetic analyses revealed multi-compartmental behaviour and a rapid distribution of BI 2536. Conclusions BI 2536 showed limited antitumour activity according to the design of this trial in five different tumour types. Derivatives of BI 2536 with a more favourable pharmacological profile are currently explored further in prospective studies.
The polo-box domain (PBD) of PLK1 determines mitotic substrate recognition and subcellular localization. Compounds that target PLK1 selectively are required due to the tumor-suppressor roles of PLK3. ...A structure-activity analysis of the PBD phosphopeptide binding motif has identified potent peptides that delineate the determinants required for mimicry by nonpeptidic inhibitors and provide insights into the structural basis for the selectivity of inhibitors for the PLK1 PBD. Fragment-ligated inhibitory peptides (FLIPs) obtained through REPLACE have been optimized to enhance in vitro binding and a systematic analysis of selectivity for PLK1 vs PLK3 has been carried out for peptides and peptidomimetics. Furthermore, these more drug-like non-ATP-competitive inhibitors had on-target engagement in a cellular context, as evidenced by stabilization of PLK1 in a thermal-shift assay and by inhibition of the phosphorylation of TCTP, a target of PLK1. Investigation in cells expressing a mutant PLK1 showed that these cells are sensitive to PBD inhibitors but dramatically resistant to clinically investigated ATP-competitive compounds. These results further validate targeting the PBD binding site in the move towards PLK1 inhibitors that are active against tumors resistant to ATP inhibitors.
Partially laterised khondalite rocks are the mining waste generated during the mining of bauxite for the production of aluminium. These wastes create environmental pollution as these are dumped at ...the mining area in huge amounts. An attempt has been made to recover the valuable material from this mining waste which are environmental friendly. The samples were collected, and a composite sample was prepared for size reduction and classification using unit operations. The finely sized material from hydrocyclone overflow was subjected to bioleaching using different microorganisms, especially bacteria. There are two types of bacterial culture methods that are selected based on the agent being cultured and the downstream use. The methods are solid media (Agar plates) and liquid media (Broth cultures). The analysis of the sample for both iron and alumina was taken by chemical method for 2 days, 4 days, 7 days, and 10 days. It is observed that the iron percentage reduced by 36.98% and alumina reduced by 38.40% by culturing the sample with microorganisms. The coloured bricks were prepared from the product and tested. The product has also been compared with standard that indicates its suitability for coloured brick preparation.
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Several families of protein kinases have been shown to play a critical role in the regulation of cell cycle progression, particularly progression through mitosis. These kinase ...families include the Aurora kinases, the Mps1 gene product and the Polo Like family of protein kinases (PLKs). The PLK family consists of five members and of these, the role of PLK1 in human cancer is well documented. PLK2 (SNK), which is highly homologous to PLK1, has been shown to play a critical role in centriole duplication and is also believed to play a regulatory role in the survival pathway by physically stabilizing the TSC1/2 complex in tumor cells under hypoxic conditions. As a part of our research program, we have developed a library of novel ATP mimetic chemotypes that are cytotoxic against a panel of cancer cell lines. We show that one of these chemotypes, the 6-arylsulfonyl pyridopyrimidinones, induces apoptosis of human tumor cell lines in nanomolar concentrations. The most potent of these compounds, 7ao, was found to be a highly specific inhibitor of PLK2 when profiled against a panel of 288 wild type, 55 mutant and 12 lipid kinases. Here, we describe the synthesis, structure activity relationship, in vitro kinase specificity and biological activity of the lead compound, 7ao.
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