Brexit threatens our access not only to drugs, 1 but also to radioisotopes, which are mostly imported from reactors in Belgium, France, and the Netherlands and are used to diagnose and treat diseases ...in about one million people in the UK each year. 2 Currently, appointments are occasionally cancelled owing to delays at border control. Euratom facilitates the time sensitive, highly regulated movement of nuclear goods, provides regulation and safeguards for the transportation and use of radioactive materials, and governs UK international nuclear cooperation agreements with European and third party countries.
Analysis of clinical trial specimens such as formalin-fixed paraffin-embedded (FFPE) tissue for molecular mechanisms of disease progression or drug response is often challenging and limited to a few ...markers at a time. This has led to the increasing importance of highly multiplexed assays that enable profiling of many biomarkers within a single assay. Methods for gene expression analysis have undergone major advances in biomedical research, but obtaining a robust dataset from low-quality RNA samples, such as those isolated from FFPE tissue, remains a challenge. Here, we provide a detailed evaluation of the NanoString Technologies nCounter platform, which provides a direct digital readout of up to 800 mRNA targets simultaneously. We tested this system by examining a broad set of human clinical tissues for a range of technical variables, including sensitivity and limit of detection to varying RNA quantity and quality, reagent performance over time, variability between instruments, the impact of the number of fields of view sampled, and differences between probe sequence locations and overlapping genes across CodeSets. This study demonstrates that Nanostring offers several key advantages, including sensitivity, reproducibility, technical robustness, and utility for clinical application.
A combination therapy approach is required to improve tumor immune infiltration and patient response to immune checkpoint inhibitors that target negative regulatory receptors. Galectin-3 is a ...β-galactoside-binding lectin that is highly expressed within the tumor microenvironment of aggressive cancers and whose expression correlates with poor survival particularly in patients with non-small cell lung cancer (NSCLC). To examine the role of galectin-3 inhibition in NSCLC, we tested the effects of galectin-3 depletion using genetic and pharmacologic approaches on syngeneic mouse lung adenocarcinoma and human lung adenocarcinoma xenografts. Galectin-3
mice developed significantly smaller and fewer tumors and metastases than syngeneic C57/Bl6 wild-type mice. Macrophage ablation retarded tumor growth, whereas reconstitution with galectin-3-positive bone marrow restored tumor growth in galectin-3
mice, indicating that macrophages were a major driver of the antitumor response. Oral administration of a novel small molecule galectin-3 inhibitor GB1107 reduced human and mouse lung adenocarcinoma growth and blocked metastasis in the syngeneic model. Treatment with GB1107 increased tumor M1 macrophage polarization and CD8
T-cell infiltration. Moreover, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules. In summary, galectin-3 is an important regulator of lung adenocarcinoma progression. The novel galectin-3 inhibitor presented could provide an effective, nontoxic monotherapy or be used in combination with immune checkpoint inhibitors to boost immune infiltration and responses in lung adenocarcinoma and potentially other aggressive cancers. SIGNIFICANCE: A novel and orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and metastasis and augments response to PD-L1 blockade.
http://cancerres.aacrjournals.org/content/canres/79/7/1480/F1.large.jpg.
The fibroblast growth factor (FGF) signaling axis is increasingly implicated in tumorigenesis and chemoresistance. Several small-molecule FGF receptor (FGFR) kinase inhibitors are currently in ...clinical development; however, the predominant activity of the most advanced of these agents is against the kinase insert domain receptor (KDR), which compromises the FGFR selectivity. Here, we report the pharmacologic profile of AZD4547, a novel and selective inhibitor of the FGFR1, 2, and 3 tyrosine kinases. AZD4547 inhibited recombinant FGFR kinase activity in vitro and suppressed FGFR signaling and growth in tumor cell lines with deregulated FGFR expression. In a representative FGFR-driven human tumor xenograft model, oral administration of AZD4547 was well tolerated and resulted in potent dose-dependent antitumor activity, consistent with plasma exposure and pharmacodynamic modulation of tumor FGFR. Importantly, at efficacious doses, no evidence of anti-KDR-related effects were observed, confirming the in vivo FGFR selectivity of AZD4547. Taken together, our findings show that AZD4547 is a novel selective small-molecule inhibitor of FGFR with potent antitumor activity against FGFR-deregulated tumors in preclinical models. AZD4547 is under clinical investigation for the treatment of FGFR-dependent tumors.
To investigate the effects of prenatal exposure to monotherapy levetiracetam, topiramate, and valproate on child cognitive functioning.
This was a cross-sectional observational study. Children ...exposed to monotherapy levetiracetam (n = 42), topiramate (n = 27), or valproate (n = 47) and a group of children born to women who had untreated epilepsy (n = 55) were enrolled retrospectively from the UK Epilepsy and Pregnancy Register. Assessor-blinded neuropsychological assessments were conducted between 5 and 9 years of age. Information was collected on demographic and health variables and adjusted for in multiple regression analyses.
In the adjusted analyses, prenatal exposure to levetiracetam and topiramate were not found to be associated with reductions in child cognitive abilities, and adverse outcomes were not associated with increasing dose. Increasing dose of valproate, however, was associated with poorer full-scale IQ (-10.6, 95% confidence interval CI -16.3 to -5.0, p < 0.001), verbal abilities (-11.2, 95% CI -16.8 to -5.5, p < 0.001), nonverbal abilities (-11.1, 95% CI -17.3 to -4.9, p < 0.001), and expressive language ability (-2.3, 95% CI -3.4 to -1.6, p < 0.001). Comparisons across medications revealed poorer performance for children exposed to higher doses of valproate in comparison to children exposed to higher doses of levetiracetam or topiramate.
Preconception counseling should include discussion of neurodevelopmental outcomes for specific treatments and their doses and women should be made aware of the limited nature of the evidence base for newer antiepileptic drugs.
The perinuclear actin cap is an important cytoskeletal structure that regulates nuclear morphology and re-orientation during front-rear polarisation. The mechanisms regulating the actin cap are ...currently poorly understood. Here, we demonstrate that STEF/TIAM2, a Rac1 selective guanine nucleotide exchange factor, localises at the nuclear envelope, co-localising with the key perinuclear proteins Nesprin-2G and Non-muscle myosin IIB (NMMIIB), where it regulates perinuclear Rac1 activity. We show that STEF depletion reduces apical perinuclear actin cables (a phenotype rescued by targeting active Rac1 to the nuclear envelope), increases nuclear height and impairs nuclear re-orientation. STEF down-regulation also reduces perinuclear pMLC and decreases myosin-generated tension at the nuclear envelope, suggesting that STEF-mediated Rac1 activity regulates NMMIIB activity to promote stabilisation of the perinuclear actin cap. Finally, STEF depletion decreases nuclear stiffness and reduces expression of TAZ-regulated genes, indicating an alteration in mechanosensing pathways as a consequence of disruption of the actin cap.
Chronic obstructive pulmonary disease (COPD) and lung cancer currently form the basis for an enormous disease burden in the developed world. As a result of changing smoking trends and tobacco use, ...regrettably, a similar picture is arising rapidly within the developing world. COPD is a recognised risk factor for lung cancer, and a significant proportion of patients diagnosed with lung cancer have COPD. An association between both conditions has long been suspected but has proven difficult to demonstrate thus far. However, the common factors between both conditions are now becoming apparent thanks to recent clinical and molecular advances. Abnormal regulation of the immune system and the establishment of chronic inflammation appear to be key events in this process. In addition, the complex interplay between genes and environment and the possibility of a genetic basis to lung cancer susceptibility in the context of COPD are becoming clearer concepts. As we begin to unravel the common pathways and molecules in the pathogenesis of both conditions, we may be able to not only identify novel strategies to prevent and treat COPD and lung cancer, but also recognise molecular markers to identify patients at high risk of developing lung cancer.
Lung cancer is the principal cause of cancer-related mortality in the developed world, accounting for almost one-quarter of all cancer deaths. Traditional treatment algorithms have largely relied on ...histologic subtype and have comprised pragmatic chemotherapy regimens with limited efficacy. However, because our understanding of the molecular basis of disease in non-small cell lung cancer (NSCLC) has improved exponentially, it has become apparent that NSCLC can be radically subdivided, or molecularly characterized, based on recurrent driver mutations occurring in specific oncogenes. We know that the presence of such mutations leads to constitutive activation of aberrant signaling proteins that initiate, progress, and sustain tumorigenesis. This persistence of the malignant phenotype is referred to as “oncogene addiction.” On this basis, a paradigm shift in treatment approach has occurred. Rational, targeted therapies have been developed, the first being tyrosine kinase inhibitors (TKIs), which entered the clinical arena > 10 years ago. These were tremendously successful, significantly affecting the natural history of NSCLC and improving patient outcomes. However, the benefits of these drugs are somewhat limited by the emergence of adaptive resistance mechanisms, and efforts to tackle this phenomenon are ongoing. A better understanding of all types of oncogene-driven NSCLC and the occurrence of TKI resistance will help us to further develop second- and third-generation small molecule inhibitors and will expand our range of precision therapies for this disease.
Focal adhesion (FA) disassembly required for optimal cell migration is mediated by microtubules (MTs); targeting of FAs by MTs coincides with their disassembly. Regrowth of MTs, induced by removal of ...the MT destabilizer nocodazole, activates the Rho‐like GTPase Rac, concomitant with FA disassembly. Here, we show that the Rac guanine nucleotide exchange factor (GEF) Sif and Tiam1‐like exchange factor (STEF) is responsible for Rac activation during MT regrowth. Importantly, STEF is required for multiple targeting of FAs by MTs. As a result, FAs in STEF‐knockdown cells have a reduced disassembly rate and are consequently enlarged. This leads to reduced speed of migration. Together, these findings suggest a new role for STEF in FA disassembly and cell migration through MT‐mediated mechanisms.
In this paper the Malliri lab identifies the Rac activator STEF as a new player in focal adhesion disassembly, a process fundamental for cell motility. The authors provide evidence that STEF/Rac signalling is required for optimal targeting of focal adhesions by microtubules, which is linked to focal adhesion disassembly.
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