Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

ORGANIC CHEMISTRY AT HIGH PRESSURE : CAN UNSATURATED BONDS SURVIVE 10 GPa ?

Quand le naphthalène en solution dans des mélanges d'alcanes ou d'alcools est irradié à des longueurs d'onde ≤ 315 nm, il est détruit par une série de réactions qui sont fortement accélérées à haute pression. Les analyses GC-MS des photoproduits recouvrés après montée à très haute pression (> 5GPa) montrent que plusieurs réactions sont impliquées : 1) la photolyse sensibilisée des molécules de solvant en radicaux alkyles et alkoxyles ; 2) la réduction du naphthalène en tétrahydronaphthalène et radicaux hydronaphthyles ; 3) la polymérisation des radicaux hydronaphthyles et alkyles en dimères, trimères et polymères ; 4) la photoaddition des radicaux du solvant sur le naphthalène ; et 5) l'échange H-D entre le naphthalène et les molécules de solvant. La variation de l'intensité d'excitation en fonction de la vitesse de disparition du naphthalène montre que l'étape photochimique primaire est la formation biphotonique des intermédiaires triplets du naphthalène sensibilisant la production des radicaux libres qui, à haute pression, sont des consommateurs efficaces de liaisons insaturées. Les conséquences de ces phénomènes (ainsi que d'autres décrits dans la littérature) sur la stabilité des composés organiques insaturés, à haute pression, sont discutées.When solutions of naphthalene in mixed alkanes or alcohols are irradiated at 315 nm or shorter wavelengths, naphthalene is destroyed by a series of reactions whose rates are greatly accelerated at high pressures. Analyses of the photoproducts recovered from diamond-anvil high pressure cells by gas chromatography-mass spectrometry demonstrate that several reactions are involved : 1) sensitized photolysis of solvent molecules to alkyl and alkoxy radicals ; 2) reduction of naphthalene to tetrahydronaphthalene and hydronaphthyl radicals ; 3) polymerization of the hydronaphthyl and alkyl radicals to dimers, trimers and higher polymers ; 4) photoaddition of solvent radicals to naphthalene ; and 5) H-D exchange between naphthalene and the solvents. The dependence of rate of disappearance of naphthalene on the excitation intensity shows that the primary photochemical step involves two-photons and triplet naphthalene intermediates that sensitize production of the free radicals which, at high pressures, are efficient consumers of unsaturated bonds. Implications of these and other phenomena described in the high pressure literature for the stabilities of unsaturated organic compounds at high pressures are discussed

Dynamic analysis and field investigation of a fluidized landslide in Guanling, Guizhou, China

On June 28, 2010, a large catastrophic landslide was triggered by a heavy rainfall in Guanling, Guizhou, China. This catastrophic event destroyed two villages and caused 99 casualties. The landslide involved the failure of about 985, 000 m[3] of sandstone from the source area. The displaced materials traveled about 1300 m with a descent of about 400 m, covering an area of 129, 000 m2 with the final volume being accumulated to be 1, 840, 000 m[3], approximately. To provide information for hazard zonation of similar type of landslides in the same area, we used a dynamic model (DAN3D) to simulate the runout behavior of the displaced landslide materials, and found that a combined frictional–Vollemy model could provide the best performance in simulating this landslide and the runout is precisely duplicated with a dynamic friction angle (ϕ) of 30° and a pore pressure ratio (ru) of 0.55 for the materials at the source area and with Vollemy parameters of friction coefficient f = 0.1 (dimensionless) and turbulent coefficient ξ = 400 m/s[2]. The simulated results indicated that the duration of the movement is estimated at about 60 s for a mean velocity 23 m/s. To examine the effectiveness of simulation by means of DAN3D and also to evaluate the reactivation potential of these displaced landslide materials depositing on the valley, we used electrical resistivity tomography (ERT) method to survey the depth and internal structure of landslide deposits. The ERT results showed that DAN3D gave a good prediction on the shape and runout distance of the landslide deposits, although the predicted maximum depths of landslide deposit on some areas were differing from those obtained by ERT method

Tunable Luminescence of CeAl11O18 Based Phosphors by Replacement of (AlO)+ by (SiN)+ and Co-Doping with Eu

A series of Si-N or Eu-Li doped CeAl11O18 and CeAl12O18N phosphors are prepared by solid–state reaction. Their structure and luminescence are researched carefully. Si-N doping with the concentration less than 8% can be successfully dissolved into CeAl11O18 crystal lattice and doesn't change the matrix structure, only resulting in crystal lattice shrinkage due to the shorter bond length for Si–N bond versus Al–O bond. It is observed that blue emission gradually decreases and UV emission becomes stronger due to the gradual disappearance of OMe ions with the increase of Si-N doping. Compared with the traditional UV emitting phosphor CeMgAl11O19, Si-N doped CeAl11O18 shows better thermal stability. The crystal structure and lattice parameters of Eu-Li codoped CeAl11O18 remain unchanged due to the large tolerance of rare-earth sites. On account of the energy transfer from UV emission of Ce3+ to Eu2+, a single overlapping blue emission with high intensity is obtained in Eu-Li codoped CeAl11O18 phosphor.RST/Radiation, Science and TechnologyApplied Science