The role of clinical imaging in oncology drug development: progress and new challenges.

In 2008, the role of clinical imaging in oncology drug development was reviewed. The review outlined where imaging was being applied and considered the diverse demands across the phases of drug development. A limited set of imaging techniques was being used, largely based on structural measures of disease evaluated using established response criteria such as response evaluation criteria in solid tumours. Beyond structure, functional tissue imaging such as dynamic contrast-enhanced MRI and metabolic measures using [18F]flourodeoxyglucose positron emission tomography were being increasingly incorporated. Specific challenges related to the implementation of imaging were outlined including standardisation of scanning across study centres and consistency of analysis and reporting. More than a decade on the needs of modern drug development are reviewed, how imaging has evolved to support new drug development demands, the potential to translate state-of-the-art methods into routine tools and what is needed to enable the effective use of this broadening clinical trial toolset. In this review, we challenge the clinical and scientific imaging community to help refine existing clinical trial methods and innovate to deliver the next generation of techniques. Strong industry-academic partnerships and pre-competitive opportunities to co-ordinate efforts will ensure imaging technologies maintain a crucial role delivering innovative medicines to treat cancer.

Flow Field-Flow Fractionation with a Thickness-Tapered Channel.

This study introduces the thickness-tapered channel design for flow field-flow fractionation (FlFFF) for the first time. In this design, the channel thickness linearly decreases along the channel axis such that the flow velocity increases down the channel. Channel thickness is an important variable for controlling retention time and resolution in field-flow fractionation. Especially, in the steric/hyperlayer mode of FlFFF, in which particles (>1 µm) migrate at elevated heights above the channel wall owing to hydrodynamic lift forces, the migration of long-retaining smaller-sized particles can be enhanced in a relatively thin channel or by increasing the migration flow rate; however, an upper size limit that can be resolved is simultaneously sacrificed. A thickness-tapered channel was constructed without a channel spacer by carving the surface of a channel block such that the channel inlet was deeper than the outlet (w = 400 → 200 µm). The performance of a thickness-tapered channel was evaluated using polystyrene standards and compared to that of a channel of uniform thickness (w = 300 µm) with a similar effective channel volume in terms of sample recovery, dynamic size range of separation, and steric transition under different flow rate conditions. The thickness-tapered channel can be an alternative to maintain the resolving power for particles with an upper large-diameter limit, faster separation of particles with a lower limit, and higher elution recovery without implementing the additional field-programming option.

Discovery of a potent, highly selective, and orally bioavailable inhibitor of CDK8 through a structure-based optimisation.

CDK8 is deregulated in multiple types of human cancer and is viewed as a therapeutic target for the treatment of the disease. Accordingly, the search for small-molecule inhibitors of CDK8 is being intensified. Capitalising on our initial discovery of AU1-100, a potent CDK8 inhibitor yet with a limited degree of kinase selectivity, a structure-based optimisation was carried out, with a series of new multi-substituted pyridines rationally designed, chemically prepared and biologically evaluated. Such endeavour has culminated in the identification of 42, a more potent CDK8 inhibitor with superior kinomic selectivity and oral bioavailability. The mechanism underlying the anti-proliferative effect of 42 on MV4-11 cells was studied, revealing that the compound arrested the G1 cell cycle and triggered apoptosis. The low risk of hepato- and cardio-toxicity of 42 was estimated. These findings merit further investigation of 42 as a targeted cancer therapeutic.

Apixaban anti-Xa level monitoring in treatment of acute upper extremity deep vein thrombosis for patient on chronic hemodialysis: a case report.

BACKGROUND: Patients on dialysis are at higher risk of major bleeding and recurrent thrombosis creating acute venous thromboembolism (VTE) treatment challenges. DOACs represent an interesting option but there are concerns of bioaccumulation and increased bleeding risk. Anti-Xa trough levels may be used to monitor for bioaccumulation but there is little data. CASE PRESENTATION: We describe a case, a 51 yo female, 36 kg on hemodialysis with a provoked acute upper extremity deep vein thrombosis in whom body habitus and calciphylaxis contraindicated the use of standard therapy. She received apixaban 2.5 mg twice daily for 6 weeks. The apixaban anti-Xa trough levels were measured weekly 12 h after the morning dose and ranged from 58 to 84 ng/mL, similar to expected levels with normal renal function. There were no adverse events in the 3 months follow-up. CONCLUSIONS: We saw no evidence of bioaccumulation indicating a potential role for low dose apixaban for acute VTE in dialysis patients.

Potent and orally bioavailable CDK8 inhibitors: Design, synthesis, structure-activity relationship analysis and biological evaluation.

CDK8 regulates transcription either by phosphorylation of transcription factors or, as part of a four-subunit kinase module, through a reversible association of the kinase module with the Mediator complex, a highly conserved transcriptional coactivator. Deregulation of CDK8 has been found in various types of human cancer, while the role of CDK8 in supressing anti-cancer response of natural killer cells is being understood. Currently, CDK8-targeting cancer drugs are highly sought-after. Herein we detail the discovery of a series of novel pyridine-derived CDK8 inhibitors. Medicinal chemistry optimisation gave rise to 38 (AU1-100), a potent CDK8 inhibitor with oral bioavailability. The compound inhibited the proliferation of MV4-11 acute myeloid leukaemia cells with the kinase activity of cellular CDK8 dampened. No systemic toxicology was observed in the mice treated with 38. These results warrant further pre-clinical studies of 38 as an anti-cancer agent.

Are breast biopsy markers underused?

INTRODUCTION: To evaluate current use of breast biopsy markers (BBM) amongst Australian and New Zealand radiologists. METHODS: Radiologists attending a national breast conference were invited to complete an online survey addressing demographics, BBM use following ultrasound, stereotactic, tomosynthesis and MRI-guided biopsy, frequency of early BBM displacement, preoperative lesion localisation (PLL) and axillary BBM use. RESULTS: Overall response rate was 52% (60/115). The majority (n = 45) 75% practiced in Australia. 98% had BBMs available in their practice, 40% reported BBM costs weren't covered by insurance. 27% would use BBMs more often if they were, with some utilising smaller gauge devices for lesion sampling to minimise need for BBM use and patient out-of-pocket costs. Ultrasound-guided procedures were associated with lower rates of clinically significant BBM displacement (P = 0.001). Considering PLL, 44% were able to perform US-guided PLL in <25% of cases. Poor sonographic visibility was the commonest reason why this wasn't possible. In the axilla, BBMs were mainly used to mark positive nodes in pre-neoadjuvant chemotherapy patients. CONCLUSION: This survey is the first to provide data on BBM use amongst a sample of predominantly Australian and New Zealand radiologists, and provides compelling evidence of significantly lower incidence of BBM displacement with US-guided procedures. Our results suggest some radiologists may hesitate to use BBMs due to cost, and this can influence their choice of biopsy technique. Provision of a Medicare item Number for BBMs may lead to increased adoption of best practice guidelines for preoperative diagnosis of breast lesions.

Vacuum phenomenon in the shoulder of a child.

A 10-year-old boy struck a car bonnet following which his left shoulder got pinned under the wheel. No life-threatening injuries were identified. However, the patient sustained extensive abrasions to the back and the left shoulder, a closed deformity of the left clavicle and a swollen, but stable right knee. The patient was neurovascularly intact globally and all joints had a full range of motion. Plain radiographs suggested a possible greenstick fracture of the left clavicle, but also free gas within the left glenohumeral joint. Concern was raised of an unidentified open injury to the joint. CT was supportive of the finding of gas within the left glenohumeral joint, but ruled out the possible greenstick fracture as a spurious finding. There were no other injuries. The gas was within the left glenohumeral joint and was consistent with vacuum phenomenon. The injury was treated expectantly and the child made a full recovery.

Correction: Oral anticoagulant re-initiation following intracerebral hemorrhage in non-valvular atrial fibrillation: Global survey of the practices of neurologists, neurosurgeons and thrombosis experts.

[This corrects the article DOI: 10.1371/journal.pone.0191137.].

Oral anticoagulant re-initiation following intracerebral hemorrhage in non-valvular atrial fibrillation: Global survey of the practices of neurologists, neurosurgeons and thrombosis experts.

BACKGROUND: While oral anticoagulants (OACs) are highly effective for ischemic stroke prevention in atrial fibrillation, intracerebral hemorrhage (ICH) remains the most feared complication of OAC. Clinical controversy remains regarding OAC resumption and its timing for ICH survivors with atrial fibrillation because the balance between risks and benefits has not been investigated in randomized trials. AIMS/HYPOTHESIS: To survey the practice of stroke neurologists, thrombosis experts and neurosurgeons on OAC re-initiation following OAC-associated ICH. METHODS: An online survey was distributed to members of the International Society for Thrombosis and Haemostasis, Canadian Stroke Consortium, NAVIGATE-ESUS trial investigators (Clinicatrials.gov identifier NCT02313909) and American Association of Neurological Surgeons. Demographic factors and 11 clinical scenarios were included. RESULTS: Two hundred twenty-eight participants from 38 countries completed the survey. Majority of participants were affiliated with academic centers, and >20% managed more than 15 OAC-associated ICH patients/year. Proportion of respondents suggesting OAC anticoagulant resumption varied from 30% (for cerebral amyloid angiopathy) to 98% (for traumatic ICH). Within this group, there was wide distribution in response for timing of resumption: 21.4% preferred to re-start OACs after 1-3 weeks of incident ICH, while 25.3% opted to start after 1-3 months. Neurosurgery respondents preferred earlier OAC resumption compared to stroke neurologists or thrombosis experts in 5 scenarios (p<0.05 by Kendall's tau). CONCLUSIONS: Wide variations in current practice exist among management of OAC-associated ICH, with decisions influenced by patient- and provider-related factors. As these variations likely reflect the lack of high quality evidence, randomized trials are direly needed in this population.

Cyclin-Dependent Kinase 8: A New Hope in Targeted Cancer Therapy?

Cyclin-dependent kinase 8 (CDK8) plays a vital role in regulating transcription either through its association with the Mediator complex or by phosphorylating transcription factors. Myriads of genetic and biochemical studies have established CDK8 as a key oncogenic driver in many cancers. Specifically, CDK8-mediated activation of oncogenic Wnt-ß-catenin signaling, transcription of estrogen-inducible genes, and suppression of super enhancer-associated genes contributes to oncogenesis in colorectal, breast, and hematological malignancies, respectively. However, while most research supports the role of CDK8 as an oncogene, other work has raised the possibility of its contrary function. The diverse biological functions of CDK8 and its seemingly context-specific roles in different types of cancers have spurred a great amount of interest and perhaps an even greater amount of controversy in the development of CDK8 inhibitors as potential cancer therapeutic agents. Herein, we review the latest landscape of CDK8 biology and its involvement in carcinogenesis. We dissect current efforts in discovering CDK8 inhibitors and attempt to provide an outlook at the future of CDK8-targeted cancer therapies.

Head and Neck Pain in Patients Presenting with Acute Aortic Dissection.

BACKGROUND: Head and neck pain is an atypical presentation of acute aortic dissection. Classic teaching associates this pain with proximal dissections, but this has not been extensively studied. METHODS: Patients enrolled in the International Registry of Acute Aortic Dissection from January 1996 to March 2015 were included in this study. We analyzed the demographics, presentation, treatment, and outcomes of Type A aortic dissection patients presenting with head and neck pain (n = 812, 25.8%) and compared it with those without these symptoms (n = 2,341, 74.2%). RESULTS: Patients with head and neck pain were more likely to be white, female, with a family history of aortic disease. Patients with head and neck pain had higher percentages of back pain (43.3% vs. 37.5%, p = 0.005) and chest pain (87.6% vs. 79.3%, p < 0.001). On imaging, a higher percentage of those with head and neck pain had arch vessel involvement (44.3% vs. 38%, p = 0.010) and intramural hematoma (11.7% vs. 8.1%, p = 0.003). Surgical management was more common in patients with head and neck pain (89.8% vs. 85.2%, p = 0.001). Regarding outcomes, patients with head and neck pain had significantly higher rates of stroke than those without head and neck pain (13% vs. 9.9%, p = 0.016); however, overall mortality was lower for those with head and neck pain (19.5% vs. 23%, p = 0.038). Those with head and neck pain only had higher overall mortality compared to those with head and neck pain with chest or back pain (34.6% vs. 19.9%, p = 0.013). A logistic regression of mortality revealed that preoperative hypotension and age > 65 years were significantly associated with increased mortality. CONCLUSION: Presence of head and neck pain in Type A dissection is associated with more arch involvement, intramural hematoma, and stroke. When isolating those with head and neck pain only, there appear to be a higher rate of comorbidity burden and higher overall mortality.

Acoustophoretic Mobility and Its Role in Optimizing Acoustofluidic Separations.

In the separation sciences, sample species are separated according to their physicochemical properties, the nature of the selective field, and, if present, the properties of the medium in which they are dissolved or suspended. Separations may be carried out on a continuous basis in microfluidic devices or split-flow thin channel (SPLITT) devices by selectively transporting species in a direction transverse to the direction of flow of the suspending fluid. Separation is achieved in the so-called transport mode according to relative differences in mobility of the species under the influence of the applied field. Gravitational, centrifugal, thermal gradient, magnetic, electric, and dielectric fields may all be used for continuous SPLITT fractionation. We present here the theory for optimizing the operation of the relatively new technique of acoustic SPLITT fractionation for the continuous separation of non-Brownian materials. The theory is based on a quantitatively defined acoustophoretic mobility that is consistent with the generalized concept of mobility proposed by Giddings. Until now, acoustophoretic mobility has almost exclusively been used as a qualitative descriptor for velocity induced by an acoustic field. The quantitative definition presented here will contribute to the advancement of all forms of acoustofluidic separations.

In Search of Novel CDK8 Inhibitors by Virtual Screening.

Aberrant activity of cyclin-dependent kinase (CDK) 8 is implicated in various cancers. While CDK8-targeting anticancer drugs are highly sought-after, no CDK8 inhibitor has yet reached clinical trials. Herein a large library of drug-like molecules was computationally screened using two complementary cascades to identify potential CDK8 inhibitors. Thirty-three hits were identified to inhibit CDK8 and seven of them were active against colorectal cancer cell lines. Finally, the primary target was confirmed using three promising hits.

Packing and the structural transformations in liquid and amorphous oxides from ambient to extreme conditions.

Liquid and glassy oxide materials play a vital role in multiple scientific and technological disciplines, but little is known about the part played by oxygen-oxygen interactions in the structural transformations that change their physical properties. Here we show that the coordination number of network-forming structural motifs, which play a key role in defining the topological ordering, can be rationalized in terms of the oxygen-packing fraction over an extensive pressure and temperature range. The result is a structural map for predicting the likely regimes of topological change for a range of oxide materials. This information can be used to forecast when changes may occur to the transport properties and compressibility of, e.g., fluids in planetary interiors, and is a prerequisite for the preparation of new materials following the principles of rational design.

Do chest compressions during simulated infant CPR comply with international recommendations?

BACKGROUND: Morbidity and mortality remain high following infant cardiac arrest. Optimal cardiopulmonary resuscitation (CPR) is therefore imperative. OBJECTIVE: Comparison of two-thumb (TT) and two-finger (TF) infant chest compression technique compliance with international recommendations. DESIGN: Randomised cross-over experimental study. METHODS: Twenty-two certified Advanced Paediatric Life Support (APLS) instructors performed 2 min continuous TT and TF chest compressions on an instrumented infant CPR manikin. Compression depth (CD), release force (RF), compression rate (CR) and duty cycles (DCs) were recorded. Quality indices were developed to calculate the proportion of compressions that complied with internationally recommended targets, and an overall quality index was used to calculate the proportion that complied with all four targets. RESULTS: Mean CD was 33 mm and 26 mm (p<0.001; target ≥36.7 mm), mean RF was 0.8 kg and 0.2 kg (p<0.001; target <2.5 kg), mean CR was 128/min and 131/min (p=0.052; target 100-120/min) and mean DCs was 61% and 53% (p<0.001; target 30-50%) for the TT and TF techniques, respectively. With the exception of RF, the majority of compressions failed to comply with targets. The TT technique improved median CD compliance (6% vs 0% (p<0.001)), while the TF technique improved median DC compliance (23% vs 0% (p<0.001)). Overall compliance with all four targets was <1% for both techniques (p=0.14). CONCLUSIONS: Compliance of APLS instructors with current international recommendations during simulated infant CPR is poor. The TT technique provided improved CD compliance, while the TF technique provided superior DC compliance. If this reflects current clinical practice, optimisation of performance to achieve international recommendations during infant CPR is called for.

Neuromuscular effects of G93A-SOD1 expression in zebrafish.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal disorder involving the degeneration and loss of motor neurons. The mechanisms of motor neuron loss in ALS are unknown and there are no effective treatments. Defects in the distal axon and at the neuromuscular junction are early events in the disease course, and zebrafish provide a promising in vivo system to examine cellular mechanisms and treatments for these events in ALS pathogenesis. RESULTS: We demonstrate that transient genetic manipulation of zebrafish to express G93A-SOD1, a mutation associated with familial ALS, results in early defects in motor neuron outgrowth and axonal branching. This is consistent with previous reports on motor neuron axonal defects associated with familial ALS genes following knockdown or mutant protein overexpression. We also demonstrate that upregulation of growth factor signaling is capable of rescuing these early defects, validating the potential of the model for therapeutic discovery. We generated stable transgenic zebrafish lines expressing G93A-SOD1 to further characterize the consequences of G93A-SOD1 expression on neuromuscular pathology and disease progression. Behavioral monitoring reveals evidence of motor dysfunction and decreased activity in transgenic ALS zebrafish. Examination of neuromuscular and neuronal pathology throughout the disease course reveals a loss of neuromuscular junctions and alterations in motor neuron innervations patterns with disease progression. Finally, motor neuron cell loss is evident later in the disease. CONCLUSIONS: This sequence of events reflects the stepwise mechanisms of degeneration in ALS, and provides a novel model for mechanistic discovery and therapeutic development for neuromuscular degeneration in ALS.

Hyperinsulinemia induces insulin resistance in dorsal root ganglion neurons.

Insulin resistance (IR) is the major feature of metabolic syndrome, including type 2 diabetes. IR studies are mainly focused on peripheral tissues, such as muscle and liver. There is, however, little knowledge about IR in neurons. In this study, we examined whether neurons develop IR in response to hyperinsulinemia. We first examined insulin signaling using adult dorsal root ganglion neurons as a model system. Acute insulin treatment resulted in time- and concentration-dependent activation of the signaling cascade, including phosphorylation of the insulin receptor, Akt, p70S6K, and glycogen synthase kinase-3ß. To mimic hyperinsulinemia, cells were pretreated with 20 nM insulin for 24 h and then stimulated with 20 nM insulin for 15 min. Chronic insulin treatment resulted in increased basal Akt phosphorylation. More importantly, acute insulin stimulation after chronic insulin treatment resulted in blunted phosphorylation of Akt, p70S6K, and glycogen synthase kinase-3ß. Interestingly, when the cells were treated with phosphatidylinositol 3-kinase pathway inhibitor, but not MAPK pathway inhibitor, chronic insulin treatment did not block acute insulin treatment-induced Akt phosphorylation. Insulin-induced Akt phosphorylation was lower in dorsal root ganglion neurons from BKS-db/db compared with control BKS-db+ mice. This effect was age dependent. Our results suggest that hyperinsulinemia cause IR by disrupting the Akt-mediated pathway. We also demonstrate that hyperinsulinemia increases the mitochondrial fission protein dynamin-related protein 1. Our results suggest a new theory for the etiology of diabetic neuropathy, i.e. that, similar to insulin dependent tissues, neurons develop IR and, in turn, cannot respond to the neurotrophic properties of insulin, resulting in neuronal injury and the development of neuropathy.