Cyclin-dependent kinases (CDKs) contribute to the cancer hallmarks of uncontrolled proliferation and increased survival. As a result, over the last two decades substantial efforts have been directed ...towards identification and development of pharmaceutical CDK inhibitors. Insights into the biological consequences of CDK inhibition in specific tumor types have led to the successful development of CDK4/6 inhibitors as treatments for certain types of breast cancer. More recently, a new generation of pharmaceutical inhibitors of CDK enzymes that regulate the transcription of key oncogenic and pro-survival proteins, including CDK9, have entered clinical development. Here, we provide the first disclosure of the chemical structure of fadraciclib (CYC065), a CDK inhibitor and clinical candidate designed by further optimization from the aminopurine scaffold of seliciclib. We describe its synthesis and mechanistic characterization. Fadraciclib exhibits improved potency and selectivity for CDK2 and CDK9 compared to seliciclib, and also displays high selectivity across the kinome. We show that the mechanism of action of fadraciclib is consistent with potent inhibition of CDK9-mediated transcription, decreasing levels of RNA polymerase II C-terminal domain serine 2 phosphorylation, the pro-survival protein Myeloid Cell Leukemia 1 (MCL1) and MYC oncoprotein, and inducing rapid apoptosis in cancer cells. This cellular potency and mechanism of action translate to promising anti-cancer activity in human leukemia mouse xenograft models. Studies of leukemia cell line sensitivity identify mixed lineage leukemia (MLL) gene status and the level of B-cell lymphoma 2 (BCL2) family proteins as potential markers for selection of patients with greater sensitivity to fadraciclib. We show that the combination of fadraciclib with BCL2 inhibitors, including venetoclax, is synergistic in leukemic cell models, as predicted from simultaneous inhibition of MCL1 and BCL2 pro-survival pathways. Fadraciclib preclinical pharmacology data support its therapeutic potential in CDK9- or CDK2-dependent cancers and as a rational combination with BCL2 inhibitors in hematological malignancies. Fadraciclib is currently in Phase 1 clinical studies in patients with advanced solid tumors (NCT02552953) and also in combination with venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) (NCT03739554) and relapsed refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (NCT04017546).
Background
Previous reports suggest that body composition parameters can be used to predict outcomes for patients with gastrointestinal (GI) cancers. However, evidence for an association with ...long-term survival is conflicting, with much of the data derived from patients with advanced disease. This study examined the effect of body composition on survival in primary operable GI cancer.
Methods
Patients with resectable adenocarcinoma of the GI tract (esophagus, stomach, colon, rectum) between 2006 and 2014 were identified from a prospective database. Computed tomography (CT) scans were analyzed using a transverse section at L3 to calculate sex-specific body composition indices for skeletal muscle, visceral fat, and subcutaneous fat. Kaplan–Meier and log-rank analysis were used to compare unadjusted survival. Multivariate survival analyses were performed using a proportional hazards model.
Results
The study enrolled 447 patients (191 woman and 256 men) with esophagogastric (OG) (
n
= 108) and colorectal (CR) (
n
= 339) cancer. Body composition did not predict survival for the OG cancer patients. Among the CR cancer patients, survival was shorter for those with sarcopenia (
p
= 0.017) or low levels of subcutaneous fat (
p
= 0.005). Older age (
p
= 0.046) and neutrophilia (
p
= 0.013) were associated with sarcopenia in patients with CR. Tumor stage (
p
= 0.033), neutrophil count (
p
= 0.011), and hypoalbuminemia (
p
= 0.023) were associated with sarcopenia in OG cancer patients. In the multivariate analysis, no single measure of body composition was an independent predictor of reduced survival.
Conclusion
Sarcopenia and reduced subcutaneous adiposity are associated with reduced survival for patients with primary operable CR cancer. However, in this study, no parameter of body composition was an independent prognostic marker when considered with age, tumor stage, and systemic inflammation.
DNA interstrand crosslinks (ICLs) are highly toxic because they block the progression of replisomes. The Fanconi Anemia (FA) proteins, encoded by genes that are mutated in FA, are important for ...repair of ICLs. The FA core complex catalyzes the monoubiquitination of FANCD2, and this event is essential for several steps of ICL repair. However, how monoubiquitination of FANCD2 promotes ICL repair at the molecular level is unknown. Here, we describe a highly conserved protein, KIAA1018/MTMR15/FAN1, that interacts with, and is recruited to sites of DNA damage by, the monoubiquitinated form of FANCD2. FAN1 exhibits endonuclease activity toward 5′ flaps and has 5′ exonuclease activity, and these activities are mediated by an ancient VRR_nuc domain. Depletion of FAN1 from human cells causes hypersensitivity to ICLs, defects in ICL repair, and genome instability. These data at least partly explain how ubiquitination of FANCD2 promotes DNA repair.
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► FAN1 is a 5′ flap endonuclease with 5′ exonuclease activity ► FAN1 is recruited to sites of DNA damage by monoubiquitinated FANCD2 ► Depletion of FAN1 causes DNA damage sensitivity and genome instability ► FAN1 is required for the late stages of ICL repair
This paper will look at two significant technological developments, one concerning the performance of optical and infrared detector systems, which are now capable of genuine photon counting ...performance, and secondly a new approach to tackling the problem of adaptive optics when only faint reference stars are available close to the target object.
The genotoxin cisplatin is commonly used in chemotherapy to treat solid tumors, yet our understanding of the mechanism underlying the drug response is limited. In a focused siRNA screen, using an ...siRNA library targeting genes involved in ubiquitin and ubiquitin-like signaling, we identified the E3 ubiquitin ligase HOIP as a key regulator of cisplatin-induced genotoxicity. HOIP forms, with SHARPIN and HOIL-1L, the linear ubiquitin assembly complex (LUBAC). We show that cells deficient in the HOIP ligase complex exhibit hypersensitivity to cisplatin. This is due to a dramatic increase in caspase-8/caspase-3-mediated apoptosis that is strictly dependent on ATM-, but not ATR-mediated DNA damage checkpoint activation. Moreover, basal and cisplatin-induced activity of the stress response kinase JNK is enhanced in HOIP-depleted cells and, conversely, JNK inhibition can increase cellular resistance to cisplatin and reverse the apoptotic hyperactivation in HOIP-depleted cells. Furthermore, we show that HOIP depletion sensitizes cancer cells, derived from carcinomas of various origins, through an enhanced apoptotic cell death response. We also provide evidence that ovarian cancer cells classified as cisplatin-resistant can regain sensitivity following HOIP downregulation. Cumulatively, our study identifies a HOIP-regulated antiapoptotic signaling pathway, and we envisage HOIP as a potential target for the development of combinatorial chemotherapies to potentiate the efficacy of platinum-based anticancer drugs.
Altered cellular metabolism is a major mechanism by which tumours support nutrient consumption associated with increased cellular proliferation. Selective dependency on specific metabolic pathways ...provides a therapeutic vulnerability that can be targeted in cancer therapy. Anti-metabolites have been used clinically since the 1940s and several agents targeting nucleotide metabolism are now well established as standard of care treatment in a range of indications. However, despite great progress in our understanding of the metabolic requirements of cancer and non-cancer cells within the tumour microenvironment, there has been limited clinical success for novel agents targeting pathways outside of nucleotide metabolism. We believe that there is significant therapeutic potential in targeting metabolic processes within cancer that is yet to be fully realised. However, current approaches to identify novel targets, test novel therapies and select patient populations most likely to benefit are sub-optimal. We highlight recent advances in technologies and understanding that will support the identification and validation of novel targets, re-evaluation of existing targets and design of optimal clinical positioning strategies to deliver patient benefit.
Background: The development of prolonged post-operative ileus (POI) remains a significant problem in the general surgical patient population. The aetiology of ileus is poorly understood and ...management options/preventative measures are currently extremely limited. The pathophysiology leading to a post-operative ileus is relatively poorly understood, and there is no validated method to estimate ileus occurrence or duration. Ileus in the post-operative period commonly occurs following major colorectal surgery and leads to painful abdominal distension, vomiting, nutritional deficit, pneumonia, prolonged hospital stays and susceptibility to hospital-acquired infection. An increased hospital stay, the burden of treatment costs and the burden on the health system highlight the importance of future research on finding definitions, preventions and predictions of ileus. Methods: A systematic literature review was performed to identify randomized controlled trials (RCTs) comparing the rate of ileus on various treatments for prolonged post-operative ileus following colorectal surgery. A confidence evaluation in a meta-analysis were performed using CINeMA. Direct and indirect comparisons of all interventions were simultaneously carried out using a network meta-analysis. The level of certainty was appraised using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. The method of assessing the risk of bias, the quality assessment, used the Cochrane Risk of Bias 2 tool (RoB2). Results: Among the seven included studies, the majority suffered from considerable within-study bias, affecting the confidence rates of study findings. Heterogeneity and incoherence made the pairwise meta-analysis and ranking of interventions unfeasible. Indirect comparisons were considered unreliable due to this incoherence. Conclusions: This systematic review, with a confidence evaluation in the network meta-analysis, determined that there is a knowledge gap in the field of study on prolonged ileus following digestive surgery. The current evidence suffers from heterogeneity and incoherence more than imprecision. There is a gap in the data on ileus occurrence in interventional trials for digestive surgery. This could inform clinicians and trialists to better appraise the current literature and plan future trials.
High-efficiency lucky imaging Mackay, Craig
Monthly notices of the Royal Astronomical Society,
06/2013, Letnik:
432, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Lucky imaging is now an established observing procedure that delivers near-diffraction-limited images in the visible on ground-based telescopes up to ∼2.5 m in diameter. Combined with low-order ...adaptive optics it can deliver a resolution several times better than that of the Hubble Space Telescope. Many images are taken at high speed as atmospheric turbulent effects appear static on these short time-scales. The sharpest images are selected, shifted and added to give a much higher resolution than is normally possible in ground-based long exposure time observations. The method is relatively inefficient as a significant fraction of the frames are discarded because of their relatively poor quality. This paper shows that a new lucky imaging processing method involving selection in Fourier space can substantially improve the selection percentages. The results show that high-resolution images with a large isoplanatic patch size may be obtained routinely both with conventional lucky imaging and with the new lucky Fourier method. Other methods of improving the sensitivity of the method to faint reference stars are also described.
The many proteins that function in the Fanconi anaemia (FA) monoubiquitylation pathway initiate replicative DNA crosslink repair. However, it is not clear whether individual FA genes participate in ...DNA repair pathways other than homologous recombination and translesion bypass. Here we show that avian DT40 cell knockouts of two integral FA genes--UBE2T and FANCM are unexpectedly sensitive to UV-induced DNA damage. Comprehensive genetic dissection experiments indicate that both of these FA genes collaborate to promote nucleotide excision repair rather than translesion bypass to protect cells form UV genotoxicity. Furthermore, UBE2T deficiency impacts on the efficient removal of the UV-induced photolesion cyclobutane pyrimidine dimer. Therefore, this work reveals that the FA pathway shares two components with nucleotide excision repair, intimating not only crosstalk between the two major repair pathways, but also potentially identifying a UBE2T-mediated ubiquitin-signalling response pathway that contributes to nucleotide excision repair.
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