Targeting OLFML3 in colorectal cancer suppresses tumor growth and angiogenesis, and increases the efficacy of anti-PD1 based immunotherapy

The role of the proangiogenic factor olfactomedin-like 3 (OLFML3) in cancer is unclear. To characterize OLFML3 expression in human cancer and its role during tumor development, we undertook tissue expression studies, gene expression analyses of patient tumor samples, in vivo studies in mouse cancer models, and in vitro coculture experiments. OLFML3 was expressed at high levels, mainly in blood vessels, in multiple human cancers. We focused on colorectal cancer (CRC), as elevated expression of OLFML3 mRNA correlated with shorter relapse-free survival, higher tumor grade, and angiogenic microsatellite stable consensus molecular subtype 4 (CMS4). Treatment of multiple in vivo tumor models with OLFML3-blocking antibodies and deletion of the Olfml3 gene from mice decreased lymphangiogenesis, pericyte coverage, and tumor growth. Antibody-mediated blockade of OLFML3 and deletion of host Olfml3 decreased the recruitment of tumor-promoting tumor-associated macrophages and increased infiltration of the tumor microenvironment by NKT cells. Importantly, targeting OLFML3 increased the antitumor efficacy of anti-PD-1 checkpoint inhibitor therapy. Taken together, the results demonstrate that OLFML3 is a promising candidate therapeutic target for CRC. </p

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

<p>Abstract</p> <p>Background</p> <p>Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics.</p> <p>Discussion</p> <p>In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.</p> <p>As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy.</p> <p>Summary</p> <p>Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.</p

Optical property measurements of turbid media in a small-volume cuvette with frequency-domain photon migration.

A frequency-domain photon migration (FDPM) technique is developed for quantitative measurement of the absorption and reduced scattering coefficients of highly turbid samples in a small-volume (0.45-ml) reflective cuvette. We present both an analytical model for the FDPM cuvette and its experimental verification, using calibrated phantoms and suspensions of living cells. FDPM model fits to experimental data demonstrate that the reduced scattering (mu(s)?) and absorption (mu(a)) coefficients can be derived with accuracies of 5-10% and 10-15%, respectively. Changing the cuvette wall reflectivity alters the frequency-dependent behavior of photon density waves (PDWs). For highly reflective wall boundaries (R(eff) &gt;/= 90-95%), PDW confinement leads to substantial enhancement in both amplitude and phase compared with identical samples in infinite media. Results from experiments on microsphere suspensions are compared with predictions from Mie theory to assess the potential of this method to interpret scattering properties in terms of scatterer size and density. Optical property measurements of biological cell suspensions are reported, and the possibility of optically monitoring cell physiology in a carefully controlled environment is demonstrated

Optical property measurements of turbid media in a small-volume cuvette with frequency-domain photon migration.

A frequency-domain photon migration (FDPM) technique is developed for quantitative measurement of the absorption and reduced scattering coefficients of highly turbid samples in a small-volume (0.45-ml) reflective cuvette. We present both an analytical model for the FDPM cuvette and its experimental verification, using calibrated phantoms and suspensions of living cells. FDPM model fits to experimental data demonstrate that the reduced scattering (mu(s)?) and absorption (mu(a)) coefficients can be derived with accuracies of 5-10% and 10-15%, respectively. Changing the cuvette wall reflectivity alters the frequency-dependent behavior of photon density waves (PDWs). For highly reflective wall boundaries (R(eff) &gt;/= 90-95%), PDW confinement leads to substantial enhancement in both amplitude and phase compared with identical samples in infinite media. Results from experiments on microsphere suspensions are compared with predictions from Mie theory to assess the potential of this method to interpret scattering properties in terms of scatterer size and density. Optical property measurements of biological cell suspensions are reported, and the possibility of optically monitoring cell physiology in a carefully controlled environment is demonstrated