Final results of urelumab, an anti-CD137 agonist monoclonal antibody, in combination with cetuximab or nivolumab in patients with advanced solid tumors.

Background: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors.

The E3 ubiquitin ligase Itch regulates death receptor and cholesterol trafficking to affect TRAIL-mediated apoptosis.

The activation of apoptosis signalling by TRAIL (TNF-related apoptosis-inducing ligand) through receptor binding is a fundamental mechanism of cell death induction and is often perturbed in cancer cells to enhance their cell survival and treatment resistance. Ubiquitination plays an important role in the regulation of TRAIL-mediated apoptosis, and here we investigate the role of the E3 ubiquitin ligase Itch in TRAIL-mediated apoptosis in oesophageal cancer cells. Knockdown of Itch expression results in resistance to TRAIL-induced apoptosis, caspase-8 activation, Bid cleavage and also promotes cisplatin resistance.

Cancer-associated fibroblasts are the main contributors to epithelial-to-mesenchymal signatures in the tumor microenvironment.

Epithelial-to-mesenchymal transition (EMT) is associated with tumor initiation, metastasis, and drug resistance. However, the mechanisms underlying these associations are largely unknown. We studied several tumor types to identify the source of EMT gene expression signals and a potential mechanism of resistance to immuno-oncology treatment.

Rapid single cell evaluation of human disease and disorder targets using REVEAL: SingleCell™.

Background: Single-cell (sc) sequencing performs unbiased profiling of individual cells and enables evaluation of less prevalent cellular populations, often missed using bulk sequencing. However, the scale and the complexity of the sc datasets poses a great challenge in its utility and this problem is further exacerbated when working with larger datasets typically generated by consortium efforts. As the scale of single cell datasets continues to increase exponentially, there is an unmet technological need to develop database platforms that can evaluate key biological hypotheses by querying extensive single-cell datasets.

Genome-wide association analysis identifies genetic correlates of immune infiltrates in solid tumors.

Therapeutic options for the treatment of an increasing variety of cancers have been expanded by the introduction of a new class of drugs, commonly referred to as checkpoint blocking agents, that target the host immune system to positively modulate anti-tumor immune response. Although efficacy of these agents has been linked to a pre-existing level of tumor immune infiltrate, it remains unclear why some patients exhibit deep and durable responses to these agents while others do not benefit. To examine the influence of tumor genetics on tumor immune state, we interrogated the relationship between somatic mutation and copy number alteration with infiltration levels of 7 immune cell types across 40 tumor cohorts in The Cancer Genome Atlas.

Estimation of flux distributions with Monte Carlo functional expansion tallies.

Monte Carlo methods provide a powerful technique for estimating the average radiation flux in a volume (or across a surface) in cases where analytical solutions may not be possible. Unfortunately, Monte Carlo simulations typically provide only integral results and do not offer any further details about the distribution of the flux with respect to space, angle, time or energy. In the functional expansion tally (FET) a Monte Carlo simulation is used to estimate the functional expansion coefficients for flux distributions with respect to an orthogonal set of basis functions.

A glycoprotein hormone expressed in corticotrophs exhibits unique binding properties on thyroid-stimulating hormone receptor.

Corticotroph-derived glycoprotein hormone (CGH), also referred to as thyrostimulin, is a noncovalent heterodimer of glycoprotein hormone alpha 2 (GPHA2) and glycoprotein hormone beta 5 (GPHB5). Here, we demonstrate that both subunits of CGH are expressed in the corticotroph cells of the human anterior pituitary, as well as in skin, retina, and testis. CGH activates the TSH receptor (TSHR); (125)I-CGH binding to cells expressing TSHR is saturable, specific, and of high affinity.

Thomson scattering and ponderomotive intermodulation within standing laser beat waves in plasma.

Electrons in a standing electromagnetic wave--an optical lattice--tend to oscillate due to the quiver and ponderomotive potentials. For sufficiently intense laser fields (Ilamda2 approximately < or = 5 x 10(17) W cm(-2) microm2) and in plasmas with sufficiently low electron densities (n approximately < or = 10(18) cm(-3)), these oscillations can occur faster than the plasma can respond. This paper shows that these oscillations result in Thomson scattering of light at both the laser and ponderomotive bounce frequencies and their harmonics as well as at mixtures of these frequencies.

Walking tree heuristics for comparative genomic alignments.

Genomic sequence data is available for an ever-increasing number of organisms, but the full meaning of this data remains an enigma. String alignment is one approach for deciphering the information contained in genetic strings. Sequences which are conserved across species will help identify genes and other important structures.