Posts Tagged ‘combination’

The quantum properties of non-point particles

Quantum theory: it’s unreal We know that everything in the universe including particles have physical size. Even so for the past 50 years, the Standard Model of particle physics which many say has given us the most complete mathematical description of the particles and forces that shape our world ignores this fact and treats them […]

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Intramolecular interactions that control voltage sensitivity in the jShak1 potassium channel from Polyorchis penicillatus [RESEARCH ARTICLE]

Nazlee Sharmin and Warren J. GallinVoltage-gated potassium ion (Kv) channel proteins respond to changes in membrane potential by changing the probability of K+ flux through an ion-selective pore. Kv channels from different paralogous and orthologous fa…

Can a trio of methods save American chestnuts?

Three methods for bringing American chestnut trees back to North American forests can now converge, […]

The post Can a trio of methods save American chestnuts? appeared first on Futurity.

Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells

Recent clinical trials using immunotherapy have demonstrated its potential to control cancer by disinhibiting the immune system. Immune checkpoint blocking (ICB) antibodies against cytotoxic-T-lymphocyte-associated protein 4 or programmed cell death protein 1/programmed death-ligand 1 have displayed durable clinical responses in various cancers. Although these new immunotherapies have had a notable effect on cancer treatment, multiple mechanisms of immune resistance exist in tumours. Among the key mechanisms, myeloid cells have a major role in limiting effective tumour immunity. Growing evidence suggests that high infiltration of immune-suppressive myeloid cells correlates with poor prognosis and ICB resistance. These observations suggest a need for a precision medicine approach in which the design of the immunotherapeutic combination is modified on the basis of the tumour immune landscape to overcome such resistance mechanisms. Here we employ a pre-clinical mouse model system and show that resistance to ICB is directly mediated by the suppressive activity of infiltrating myeloid cells in various tumours. Furthermore, selective pharmacologic targeting of the gamma isoform of phosphoinositide 3-kinase (PI3Kγ), highly expressed in myeloid cells, restores sensitivity to ICB. We demonstrate that targeting PI3Kγ with a selective inhibitor, currently being evaluated in a phase 1 clinical trial (NCT02637531), can reshape the tumour immune microenvironment and promote cytotoxic-T-cell-mediated tumour regression without targeting cancer cells directly. Our results introduce opportunities for new combination strategies using a selective small molecule PI3Kγ inhibitor, such as IPI-549, to overcome resistance to ICB in patients with high levels of suppressive myeloid cell infiltration in tumours.

Advanced Composite Materials

  Composites materials is basically the combining of unique properties of materials to have synergistic effects. A combination of materials is needed to adapt to certain properties for any application area. There is an everlasting desire t…

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