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Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors. Healthy cells in the human body can become cancerous if they gain genetic mutations that allow them to rapidly grow and divide. Some types of cancer respond better to drug treatments than others and tumors often develop resistance to a particular drug treatment after a while. Because of this, researchers are always searching for new molecules to develop into anticancer drugs. Recently, a team of researchers identified some small molecules that could inactivate two closely related proteins called CDK8 and CDK19. CDK8 is essential for the WNT signaling pathway – which enables cells to communicate with one another – and has been extensively studied in various cancers. Previous studies indicate that this protein can either promote or inhibit the growth of tumors, depending on the type and stage of the cancer. Furthermore, CDK8 regulates a type of molecular switch called a “super-enhancer”, which controls the activity of many genes. In contrast, the role of CDK19 in cells was not as well understood. Here Clarke, Ortiz-Ruiz et al. investigated whether two different classes of small molecules that target CDK8 and CDK19 (referred to as “prototype CDK8/19 drugs”) could inhibit the growth of cancers, and whether they have any harmful side effects on healthy cells. For the experiments, human cancer cells were implanted into mice. Treating these mice with prototype CDK8/19 drugs inhibited the activity of CDK8 and CDK19 in the cancer cells and slowed the growth of colorectal tumors. A type of blood cancer called acute myeloid leukaemia was particularly sensitive to the drugs. However, Clarke, Ortiz-Ruiz et al. also observed that the prototype drugs altered the activity of many genes with roles in healthy tissues such as immune, bone and stem cells. Further experiments in mice and cells grown in the laboratory confirmed that these prototype drugs have adverse effects on healthy intestinal and bone marrow stem cells and trigger changes to immune cells. These concerning side effects were also evident when the prototype drugs were tested in rats and dogs. Furthermore, the experiments indicate that there is not a suitable range of doses of these drugs in which the therapeutic benefits outweigh the toxic side effects. Clarke, Ortiz-Ruiz et al. conclude that the clinical development of CDK8/19 drugs will be extremely challenging and that their prototype drugs would not currently be suitable for use as cancer treatments. However, the small molecules they describe will be important probes in research to study exactly how CDK8/19 regulate gene activity in both healthy cells and cancers.

Background Wnt/β-catenin signaling is often portrayed as a simple pathway that is initiated by Wnt ligand at the cell surface leading, via linear series of interactions between ‘core pathway’ members, to the induction of nuclear transcription from genes flanked by β-catenin/TCF transcription factor binding sites. Wnt/β-catenin signaling is also regulated by a much larger set of ‘non-core regulators’. However the relationship between ‘non-core regulators’ is currently not well understood. Aberrant activation of the pathway has been shown to drive tumorgenesis in a number of different tissues. Methods Mammalian cells engineered to have a partially-active level of Wnt/β-catenin signaling were screened by transfection for proteins that up or down-regulated a mid-level of TCF-dependent transcription induced by transient expression of an activated LRP6 Wnt co-receptor (∆NLRP). Results 141 novel regulators of TCF-dependent transcription were identified. Surprisingly, when tested without ∆NLRP activation, most up-regulators failed to alter TCF-dependent transcription. However, when expressed in pairs, 27 % (466/1170) functionally interacted to alter levels of TCF-dependent transcription. When proteins were displayed as nodes connected by their ability to co-operate in the regulation of TCF-dependent transcription, a network of functional interactions was revealed. In this network, ‘core pathway’ components (Eg. β-catenin, GSK-3, Dsh) were found to be the most highly connected nodes. Activation of different nodes in this network impacted on the sensitivity to Wnt pathway small molecule antagonists. Conclusions The ‘functional connectome’ identified here strongly supports an alternative model of the Wnt pathway as a complex context-dependent network. The network further suggests that mutational activation of highly connected Wnt signaling nodes predisposed cells to further context-dependent alterations in levels of TCF-dependent transcription that may be important during tumor progression and treatment.

Chemoproteomic studies have revealed that a Wnt-pathway inhibitor, CCT251545, is a potent and selective small-molecule chemical probe that inhibits the Mediator complex–associated protein kinases CDK8 and CDK19 through a type 1 binding mode and modulates the growth of Wnt-dependent tumors. There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT pathway discovered through cell-based screening, is a potent and selective chemical probe for the human Mediator complex–associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates a type 1 binding mode involving insertion of the CDK8 C terminus into the ligand binding site. In contrast to type II inhibitors of CDK8 and CDK19, CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogs alter WNT pathway–regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. Consistent with this, we find that phosphorylation of STAT1 SER727 is a biomarker of CDK8 kinase activity in vitro and in vivo . Finally, we demonstrate in vivo activity of CCT251545 in WNT-dependent tumors.

Yanick Crow and colleagues show that mutations in CTC1 , which encodes a homolog of a yeast telomere maintenance protein, cause Coats plus, a highly pleiotropic disorder sharing phenotypic overlap with dyskeratosis congenita and other disorders of telomere maintenance. Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1 , encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.

Maritime safety relies on navigation, detection, and radio communication technologies that function through electromagnetic radiation. Propagation of electromagnetic radiation can be impacted by a disruptive phenomenon known as ducting. Our four-week study using a X-band coastal radar and various meteorological and marine observations, including vertical profiles of temperature, humidity and wind, in early spring 2022 concluded that the combination of measurements at the Utö observatory provides a reliable means of detecting ducting in the Archipelago Sea. The modified refractivity calculated from the vertical profiles for the 22–59 m and 32–59 m altitude layers and coastal radar over-the-horizon observations agree 77% and 85% of the time, respectively. As such, the modified refractivity gradient can be considered a good indicator for over-the-horizon detection with the Utö coastal radar over the open sea. The horizontal wind profiles also revealed a low-level jet at the radar height that often coincided with the ducting observations. To quantify the results, we created an empirical ducting index which showed that ducting is spatially variable, showing the capabilities of the Utö observatory for research oriented towards monitoring and improving maritime safety and security.

During the first UK national coronavirus pandemic lockdown (Mar-Jul 2020), alcohol sales increased 30% in supermarkets. Surveys reported that 20% of people increased their alcohol consumption and numbers of high-risk drinkers increased by 13%. Post-lockdown, clinicians noted high numbers of alcohol-related liver disease (ArLD)-related admissions. We hypothesised that greater alcohol consumption in high-risk drinkers contributed to this increase. We conducted a national service evaluation to document the number and severity of unplanned ArLD hospital admissions pre- and post-lockdown.We performed a retrospective service evaluation in 28 UK hospitals of all unplanned admissions during a one-week period in August 2019 and the same period in August 2020. The protocol was approved by the lead site’s Clinical Audit Department and registered at participating sites. We applied a validated coding algorithm that more accurately identifies ArLD admissions than using only ArLD codes in the primary diagnosis.1 Eligible cases were manually reviewed and data extracted into a pre-designed collection tool. Data collected included demographics, diagnosis, alcohol use and liver disease severity scores, which were compared between evaluation periods.There was an 18% absolute increase in unplanned hospital admissions for patients with ArLD in the evaluation period in 2020 compared to 2019 (263 vs 223). Demographics were similar between the two periods (mean age 55; 37% female). In-hospital mortality was similar (9.0% vs 7.2%) and there were no differences between proportions of patients with complications of liver disease including variceal bleeding and alcoholic hepatitis. Patients in both evaluation periods had similar severity of liver disease with mean Child Pugh score of 8 and MELD 14. Those with alcoholic hepatitis had mean MELD 20 (SD 7.5) and discriminant function 90 (SD 70).In the post-lockdown period, there were more active alcohol drinkers (151 vs 196; 75% vs 68%) than pre-lockdown. Mean consumption per patient was higher (154 vs 127 units alcohol/week; p=0.02). More patients reported drinking spirits post- vs pre-lockdown (31% vs 22%; p=0.06).This national service evaluation demonstrates an increase in unplanned ArLD hospital admissions post-lockdown with patients reporting heavier alcohol use. Although there were no differences in clinical presentations or outcomes, these patients have advanced liver disease with high short-term mortality. These data suggest the pandemic has disproportionately affected high-risk drinkers and demonstrate the heavy burden of ArLD in the UK. There is an ongoing need to develop long-term strategies to improve these patients’ outcomes.ReferenceKallis, et al. Aliment Pharm Therap 2020;52:182–95.

ObjectivesMalignant mesothelioma is an uncommon cancer associated with asbestos exposure, predominantly occupational. Asbestos has been banned in Australia since 2003 but mesothelioma has a long latency and incident cases continue to present. The Australian Mesothelioma Registry was incepted to collect systematic data about incidence and mortality alongside asbestos exposure.MethodsBenefiting from the Australian national system of cancer notification, all incident cases of mesothelioma in all states and territories are fast-tracked and notified regularly. Notified patients are contacted asking for consent to collect exposure information, initially by postal questionnaire and subsequently by telephone interview. Age-standardised annual incidence rates and mortality rates were calculated. Asbestos exposure was categorised as occupational, non-occupational, neither or, both; and as low, or high, probability of exposure.ResultsMesothelioma incidence appears to have peaked. The age-standardised incidence rates have declined steadily since the early 2000s (peaking in males at 5.9/100 000 and in all-persons at 3.2/100 000), driven by rates in males, who comprise the majority of diagnosed cases. Rates in women have remained fairly stable since that time. Age-standardised mortality rates have followed similar trends. Mesothelioma remains the most common in those aged over 80 years. Nearly all (94%) cases were linked with asbestos exposure (78% occupational in men; 6.8% in women).ConclusionsWith effective control of occupational asbestos use, the decline in age-standardised incidence and death rates has occurred. Incidence rates among women, in whom occupational asbestos exposure is rarely detectable, remain unchanged, pointing to the role of household and /or environmental asbestos exposure.

Background: Radiofrequency ablation (RFA) is an established modality for percutaneous ablation of non-small cell lung cancer (NSCLC) in medically inoperable patients but is underutilized clinically due to side effects. We have developed a novel, completely endobronchial RFA catheter with an externally cooled electrode. Objectives: The objective of this study was to establish the safety and feasibility of bronchoscopic RFA using a novel, externally cooled catheter for ablation of peripheral NSCLC. Methods: Patients with stage I biopsy-confirmed NSCLC underwent bronchoscopic RFA of tumour 7 days prior to lobectomy. The RFA catheter was delivered bronchoscopically to peripheral NSCLC lesions, guided by radial endobronchial ultrasound, with positioning confirmed using intra-procedural cone beam CT. Pre-operative CT chest and histologic examination of resected specimens were used to establish distribution/uniformity of ablation and efficacy of tumour ablation. Results: RFA in the first patient was complicated by dispersal of heated saline due to cough, resulting in ICU admission. The patient recovered fully and underwent uncomplicated lobectomy. Subsequently, the protocol was altered to mandate neuromuscular blockade with a pre-determined dose escalation, with algorithm-restricted energy (kJ) and irrigated saline volume (mL) constraints. A further 10 patients consented and seven underwent successful bronchoscopic RFA of peripheral NSCLC. No significant adverse events were noted. Ablation zone included tumour in all cases (proportion of tumour ablated ranged 8–72%), with uniform necrosis of tissue within ablation zones observed at higher energy levels. Ablation zone diameter correlated with RFA energy delivered (R 2 = 0.553), with maximum long axis diameter of ablation zone 3.1 cm (22.9 kJ). Conclusion: Bronchoscopic RFA using an externally cooled catheter is feasible, appears safe, and achieves uniform ablation within the treatment zone. Uncontrolled escape of heated saline poses a major safety risk but can be prevented procedurally through neuromuscular blockade and by limiting irrigation.