Compression therapy in patients with venous leg ulcers: a best practice implementation project.

INTRODUCTION AND OBJECTIVES: Venous leg ulcers are the most common ulcerations of the lower extremities. Compression is the most important consideration and the gold standard treatment for venous leg ulcers. This implementation project aimed to promote best practices in the management of venous leg ulcers in a rural community-care setting. METHODS: This project was guided by the JBI Evidence Implementation Framework, which is grounded in audit and feedback processes, along with a structured approach to identifying and managing barriers to compliance with recommended best practices. RESULTS: Compliance with best practices increased for most audit criteria. The use of compression therapy increased from 16.7% to 60%, documentation increased from 6.7% to 50%, replacement of compression bandages from 6.7% to 60%, patient education from 0% to 46.7%, and holistic assessment from 0% to 13%. However, compliance for individualized interventions to promote adherence remained at 0%. CONCLUSIONS: This project succeeded in introducing compression therapy as a basic treatment for venous ulcers. However, continued improvement in the care for venous ulcers and guarantee of long-term implementation of evidence are necessary. SPANISH ABSTRACT: http://links.lww.com/IJEBH/A212.

ERK5 Interacts with Mitochondrial Glutaminase and Regulates Its Expression.

Many of the biological processes of the cell, from its structure to signal transduction, involve protein-protein interactions. On this basis, our aim was to identify cellular proteins that interact with ERK5, a serine/threonine protein kinase with a key role in tumor genesis and progression and a promising therapeutic target in many tumor types. Using affinity chromatography, immunoprecipitation, and mass spectrometry techniques, we unveiled an interaction between ERK5 and the mitochondrial glutaminase GLS in pancreatic tumor cells. Subsequent co-immunoprecipitation and immunofluorescence studies supported this interaction in breast and lung tumor cells as well. Genetic approaches using RNA interference techniques and CRISPR/Cas9 technology demonstrated that the loss of ERK5 function led to increased protein levels of GLS isoforms (KGA/GAC) and a concomitant increase in their activity in tumor cells. It is well known that the tumor cell reprograms its intermediary metabolism to meet its increased metabolic needs. In this sense, mitochondrial GLS is involved in the first step of glutamine catabolism, one of the main energy sources in the context of cancer. Our data suggest that ERK5 contributes to the regulation of tumor cell energy metabolism via glutaminolysis.

Editorial: La importancia del conocimiento / Editorial: The importance of knowledge

No disponible

Factors that influence the university's inclusive educational processes: perceptions of university professors.

BACKGROUND: Training in attention to diversity is a key aspect for achieving the inclusion of students with special educational needs in higher education for these students to have access to the same rights as any other student. AIMS: To determine, through the perceptions of university professors, if the existence of barriers that arise in the teaching-learning process is determined by various factors of interest such as gender, training in attention to diversity, and, even, the attitudes that the professors present before the inclusion of these students. METHODS AND PROCEDURES: The research was carried out in eight universities in Andalusia (Spain), using as the main method of data collection a validated survey, the APTD Scale (Accessibility, Processes, Training, Demand), with the participating sample of 580 university professors. OUTCOMES AND RESULTS: The university professors generally agree to perform inclusive actions in their teaching-learning process, although a significant association between variables. CONCLUSIONS AND IMPLICATIONS: The study includes a series of perceptions that may help other university professors to make their practice more inclusive.

De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder.

The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder. Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects; a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals. All predicted substitutions localize to the ATP-binding pocket of the kinase domain. Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism. Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing or visual impairments. To evaluate the functional impact of the mutations, we measured phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfected with wild-type (WT) or mutant CDK8 constructs. These experiments demonstrated a reduction in STAT1 phosphorylation by all mutants, in most cases to a similar extent as in a kinase-dead control. We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic similarity to syndromes associated with mutations in other subunits of the Mediator kinase module, indicating probable overlap in pathogenic mechanisms.

Assessment of chronic wounds in adults: an integrative review. / Valoración de las heridas crónicas en el adulto: una revisión integrativa.

OBJECTIVE: To identify the main aspects that should be assessed in adults with chronic wounds. METHOD: This was an integrative review of the scientific literature published between 2010 and early 2015 in the PubMed and Web of Science databases. RESULTS: Few studies exclusively address wound assessment. However, the review found many aspects to consider when assessing individuals with ulcers, grouped as follows: factors that significantly affect healing or the development of new wounds (age, nutritional status, functional capacity, or comorbidities), pyschosocial factors, and wound characteristics (location, size, depth, type of tissue, time of evolution). CONCLUSION: The literature search did not result in any one aspect that must be considered when assessing chronic wounds, but a complex interaction of factors that include both physiological and social and psychological elements. Professionals should be aware of this multifactorial approach to achieve early detection of the development and evolution of ulcers and to intervene accordingly.

The impact of axillary ultrasound with biopsy in overtreatment of early breast cancer.

PURPOSE: (a) To compare the axillary tumor burden detected by fine-needle aspiration cytology (FNAC) versus sentinel lymph node biopsy (SLNB). (b) To evaluate the relationship between axillary tumor burden and the number of suspicious lymph nodes detected by axillary ultrasonography (US). (c) To calculate the false-positive and false-negative rates for FNAC in patients fulfilling ACOSOG Z0011 criteria. METHODS: Retrospective multicenter cross-sectional study of 355 pT1 breast cancers. SLNB and axillary lymph node dissection (ALND) were gold standards. Low axillary burden (≤2 positive lymph nodes); high burden (>2 positive lymph nodes). Patients ACOSOG Z0011: false-positive (positive FNAC+low burden), false-negative (negative FNAC+high burden). RESULTS: High axillary burden: in entire series 38.5% FNAC+ vs. 5.7% SLNB+ (p<0.0001). In subgroup fulfilling ACOSOG Z0011 criteria: 45.5% vs 6.7%, respectively (p<0.001). 61 positive axillary US. With 1 suspicious node on axillary US: 95.6% had ≤2 involved nodes (including pN0); with 2 suspicious nodes: 60% had >2 involved nodes. In ACOSOG Z0011 patients, with 1 suspicious node, 93.7% had ≤2 involved nodes. Of the 37 FNAC in ACOSOG Z0011patients: 54.5% false-positives for high burden; 3.8% false-negatives. CONCLUSIONS: FNAC-positive tumors have greater axillary burden, even in patients fulfilling ACOSOG Z0011 criteria. Using axillary US/FNAC to triage patients meeting Z0011 criteria may result in axillary overtreatment. The number of suspicious nodes seen in axillary US is related with the final axillary burden and should be taken into account when deciding to do FNAC in patients fulfilling ACOSOG Z0011 criteria.

Valoración de las heridas crónicas en el adulto: una revisión integrativa / Avaliação das feridas crônicas no adulto: uma revisão integrativa / Assessment of chronic wounds in adults: an integrative review

RESUMEN Objetivo: Identificar los principales aspectos a valorar en personas adultas con heridas crónicas. Método: Revisión integrativa de la literatura científica publicada, entre 2010 y principios del año 2015, en las bases de datos PubMed y Web Of Science. Resultados: Existe un número muy limitado de estudios que se centraran exclusivamente en la valoración de las heridas. Sin embargo, se encontraron muchos aspectos a tener en cuenta en la valoración de personas con úlceras. Por lo que, estos aspectos fueron agrupados en: factores que afectaban significativamente a la cicatrización o desarrollo de nuevas heridas (como la edad, el estado nutricional, la capacidad funcional o la presencia de cormobilidades), factores psicosociales y aspectos relacionados con la lesión (localización, tamaño, profundidad, tipo de tejido, tiempo de evolución). Conclusión: En general, no se ha encontrado un aspecto único que se deba contemplar en la valoración de las heridas crónicas, sino una compleja interacción de factores que incluyen tanto aspectos fisiológicos, como sociales y psicológicos. De modo que, los profesionales deben ser conscientes de este enfoque multifactorial; para reconocer tempranamente el desarrollo y la evolución de la úlcera, e intervenir consecuentemente.

RESUMO Objetivo: Identificar os principais aspectos a ser avaliados em pessoas adultas com feridas crônicas. Método: Revisão integrativa da literatura científica publicada, entre 2010 e princípios do ano 2015, nas bases de dados PubMed e Web Of Science. Resultados: Existe um número muito limitado de estudos que se centraram exclusivamente na avaliação das feridas. No entanto, foram encontrados muitos aspectos a levar em conta na avaliação de pessoas com úlceras. Portanto, esses aspectos foram agrupados em: fatores que afetavam significativamente a cicatrização ou desenvolvimento de novas feridas (como idade, estado nutricional, capacidade funcional ou presença de comorbidades), fatores psicossociais e aspectos relacionadas à lesão (localização, tamanho, profundidade, tipo de tecido, tempo de evolução). Conclusão: Em geral, não foi encontrado um aspecto único que deva ser contemplado na avaliação das feridas crônicas, mas sim uma complexa interação de fatores que incluem tanto aspectos fisiológicos, quanto sociais e psicológicos. De modo que os profissionais devem ser conscientes desse enfoque multifatorial, para reconhecer precocemente o desenvolvimento e a evolução da úlcera e fazer a consequente intervenção.

ABSTRACT Objective: To identify the main aspects that should be assessed in adults with chronic wounds. Method: This was an integrative review of the scientific literature published between 2010 and early 2015 in the PubMed and Web of Science databases. Results: Few studies exclusively address wound assessment. However, the review found many aspects to consider when assessing individuals with ulcers, grouped as follows: factors that significantly affect healing or the development of new wounds (age, nutritional status, functional capacity, or comorbidities), pyschosocial factors, and wound characteristics (location, size, depth, type of tissue, time of evolution). Conclusion: The literature search did not result in any one aspect that must be considered when assessing chronic wounds, but a complex interaction of factors that include both physiological and social and psychological elements. Professionals should be aware of this multifactorial approach to achieve early detection of the development and evolution of ulcers and to intervene accordingly.

Atención a una cuidadora mediante procesos asistenciales integrados / Care for a caregiver through integrated healthcare processes

La población está envejeciendo en los últimos años, y con ello el número de personas depen-dientes, siendo impensable hablar de dependencia sin hablar del cuidador informal. Por lo que, lo/as cuidadores/as han sido incluido/as en los procesos asistenciales integrados para poder conseguir continuidad en los cuidados. De este modo, se presenta el caso clínico de una mujer de 47 años, cuidadora de su suegra, que tras acudir a la consulta de enfermería y reali-zarle una valoración integral, fue diagnosticada de: Cansancio del rol del cuidador y estrés por sobrecarga. Se llevaron a cabo distintas intervenciones que consistían en dar apoyo emo-cional, educación sanitaria y facilitar recursos. Como consecuencia, los resultados fueron satisfactorios, concluyendo que la detección del cansancio del rol de cuidador es crucial por la repercusión que tiene sobre la persona dependiente y el propio cuidador. Palabras clave: cuidadores, planificación de atención al paciente, enfermedad de alzheimer, enfermería en salud comunitaria.

The population is aging in recent years, and with this the number of dependents is too. It is unthinkable to talk about dependence without talking about the informal caregiver. Therefo-re, the caregivers have been included in the integrated healthcare processes in order to achie-ve continuity in care. So, the clinical case of a 47-year-old woman who takes care of her mother-in-law is presented. She was diagnosed with tiredness of the caregiver's role and stress due to overload after attending the nursing consultation and carrying out a comprehen-sive assessment. Different interventions of giving emotional support, health education and facilitating resources were performed. The results were satisfactory, concluding that the detection of tiredness of the role of caregiver is crucial because of the impact it has on the dependent person and the caregiver.

Assessing the mechanism and therapeutic potential of modulators of the human Mediator complex-associated protein kinases.

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.

Plan de cuidados sobre un caso relacionado con el proceso asistencial integrado "atención a pacientes pluripatológicos" / Care plan about a case related to the integrated care process "care for multi-pathological patients"

Las enfermedades crónicas son la principal causa de muerte en el mundo, habiendo pacientes con dos o más enfermedades crónicas que precisan de un abordaje sanitario más complejo. Se describe el caso de un paciente pluripatológico que acude a la consulta de enfermería para el seguimiento de sus patologías. Se le realizó un plan de cuidados basado en el Proceso Asistencial Integrado Atención a Pacientes Pluripatológicos. Los principales diagnósticos de enfermería estaban relacionados con el régimen terapéutico y su conducta. Los resultados obtenidos fueron satisfactorios. La labor de la enfermera comunitaria como educadora para la salud es primordial ya que previene la aparición de nuevas patologías y el empeoramiento de las ya existentes.

Chronic diseases are the leading cause of death in the world. Patients with two or more chronic diseases require a more complex sanitary approach. The case of a multi-pathological patient who goes to the nursing consultation for the follow-up of his pathologies is described. A care plan was made based on the Integrated Care Process for multi-pathological patients. The main nursing diagnoses are related to the therapeutic process and its behavior. The results were satisfactory. The work of the community nurse as an educator for health is paramount since it prevents the appearance of new pathologies and the commitment of those already existing.

Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening.

The mediator complex-associated cyclin dependent kinase CDK8 regulates ß-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies.

Diagnostic Accuracy and Impact on Management of Ultrasonography-Guided Fine-Needle Aspiration to Detect Axillary Metastasis in Breast Cancer Patients: A Prospective Study.

BACKGROUND: The axillary nodal status is essential to determine the stage of disease at diagnosis. Our aim was to prospectively assess the diagnostic accuracy of ultrasonography-guided fine-needle aspiration (US-FNA) for the detection of metastasis in axillary lymph nodes in patients with breast cancer (BC) and its impact on the therapeutic decision. MATERIALS AND METHODS: Ultrasonography (US) was performed in 407 axillae of 396 patients who subsequently underwent surgery. US-FNA was conducted when lymph nodes were detected by US. Axillary dissection (AD) was performed when US-FNA was positive for metastasis. Patients with negative US-FNA and breast tumors of 30 mm in size were candidates for selective sentinel lymph node biopsy (SLNB). The anatomopathological results of AD or SLNB were used as reference tests. RESULTS: Lymph nodes were detected by US in 207 (50.8%) axillae. Of these, US-FNA was performed on 180 (86.9%). 94 axillae (52.2%) were positive for carcinoma and 79 women received AD. US-FNA had 77.5% sensitivity, 100% specificity, 100% positive predictive value, 69.3% negative predictive value, and 85.1% diagnostic accuracy. US-FNA avoided SLNB in 18.1% of patients who underwent AD. CONCLUSIONS: Axillary US-FNA is an accurate technique in the staging of patients with BC. It allows reducing the number of SLNB and, when positive, offers a fast and useful tool.

Archaeal and bacterial community dynamics and bioprocess performance of a bench-scale two-stage anaerobic digester.

Two-stage technologies have been developed for anaerobic digestion of waste-activated sludge. In this study, the archaeal and bacterial community structure dynamics and bioprocess performance of a bench-scale two-stage anaerobic digester treating urban sewage sludge have been studied by the means of high-throughput sequencing techniques and physicochemical parameters such as pH, dried sludge, volatile dried sludge, acid concentration, alkalinity, and biogas generation. The coupled analyses of archaeal and bacterial communities and physicochemical parameters showed a direct relationship between archaeal and bacterial populations and bioprocess performance during start-up and working operation of a two-stage anaerobic digester. Moreover, results demonstrated that archaeal and bacterial community structure was affected by changes in the acid/alkalinity ratio in the bioprocess. Thus, a predominance of the acetoclastic methanogen Methanosaeta was observed in the methanogenic bioreactor at high-value acid/alkaline ratio, while a predominance of Methanomassilicoccaeceae archaea and Methanoculleus genus was observed in the methanogenic bioreactor at low-value acid/alkaline ratio. Biodiversity tag-iTag sequencing studies showed that methanogenic archaea can be also detected in the acidogenic bioreactor, although its biological activity was decreased after 4 months of operation as supported by physicochemical analyses. Also, studies of the VFA producers and VFA consumers microbial populations showed as these microbiota were directly affected by the physicochemical parameters generated in the bioreactors. We suggest that the results obtained in our study could be useful for future implementations of two-stage anaerobic digestion processes at both bench- and full-scale.

Comparison of bacterial communities of conventional and A-stage activated sludge systems.

The bacterial community structure of 10 different wastewater treatment systems and their influents has been investigated through pyrosequencing, yielding a total of 283486 reads. These bioreactors had different technological configurations: conventional activated sludge (CAS) systems and very highly loaded A-stage systems. A-stage processes are proposed as the first step in an energy producing municipal wastewater treatment process. Pyrosequencing analysis indicated that bacterial community structure of all influents was similar. Also the bacterial community of all CAS bioreactors was similar. Bacterial community structure of A-stage bioreactors showed a more case-specific pattern. A core of genera was consistently found for all influents, all CAS bioreactors and all A-stage bioreactors, respectively, showing that different geographical locations in The Netherlands and Spain did not affect the functional bacterial communities in these technologies. The ecological roles of these bacteria were discussed. Influents and A-stage bioreactors shared several core genera, while none of these were shared with CAS bioreactors communities. This difference is thought to reside in the different operational conditions of the two technologies. This study shows that bacterial community structure of CAS and A-stage bioreactors are mostly driven by solids retention time (SRT) and hydraulic retention time (HRT), as suggested by multivariate redundancy analysis.

Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.

The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.

The impact of preoperative axillary ultrasonography in T1 breast tumours.

OBJECTIVES: To (a) determine the diagnostic validity of axillary ultrasound (AUS) in pT1 tumours and whether fine-needle aspiration (FNA) improves its diagnostic performance, and (b) determine the negative predictive value (NPV) of AUS in a simulation environment (cutoff: two lymph nodes with macrometastases) in patients fulfilling American College of Surgeons Oncology Group (ACOSOG) Z0011 criteria. MATERIALS AND METHODS: This retrospective multicentre cross-sectional study analysed diagnostic accuracy in 355 pT1 breast cancers. All patients underwent AUS; visible nodes underwent FNA regardless of their AUS appearance. Sentinel node biopsy and axillary lymph node dissection (ALND) were gold standards. Data were analysed considering micrometastases 'positive' and considering micrometastases 'N negative'. The simulation environment included all patients fulfilling ACOSOG Z0011 criteria. RESULTS: Axillary involvement: 22.8 %; AUS sensitivity: 46.9 % (Nmic positive)/66.7 % (Nmic negative); AUS+FNA sensitivity: 52.6 % (pNmic positive)/72.0 % (pNmic negative). In the simulation environment, AUS had 75.0 % sensitivity, 88.9 % specificity and 99.2 % NPV. CONCLUSION: AUS has moderate sensitivity in T1 tumours. As ALND is unnecessary in micrometastases, considering micrometastases 'N negative' increases the practical impact of AUS. In patients fulfilling ACOSOG Z0011 criteria, AUS alone can predict cases unlikely to benefit from ALND. KEY POINTS: • AUS+FNA can predict axillary involvement, thus avoiding SNB. • Not all patients with axillary involvement need ALND. • Axillary tumour load determines axillary management. • AUS could classify patients according to axillary load.

Impact of methionine on a partial-nitritation biofilter.

It has been demonstrated that an anaerobic digestion process cannot attain an efficient removal of several amino acids, with methionine being one of the most persistent of these. Thus, the effect that methionine amino acid has over the partial-nitritation process with fixed-biofilm configuration in terms of performance and bacterial community dynamics has been investigated. With respect to the performance with no addition, 100 mg/L methionine loading decreased ammonium oxidation efficiency in 60% and 100% at concentrations of 300 and 500 mg/L methionine, respectively. Bacterial biomass sharply increased by 30, 65, and 230% with the addition of 100, 300, and 500 mg/L methionine, respectively. Bacterial community analysis showed that methionine addition supported the proliferation of a diversity of heterotrophic genera, such as Lysobacter and Micavibrio, and reduced the relative abundance of ammonium oxidizing genus Nitrosomonas. This research shows that the addition of methionine affects the performance of the partial-nitritation process. In this sense, amino acids can pose a threat for the of partial-nitritation process treating anaerobic digester supernatant at full-scale implementation.

A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.

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.