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BackgroundThe erosion of the early mortality advantage of elective endovascular aneurysm repair (EVAR) compared with open repair of abdominal aortic aneurysm remains without a satisfactory explanation.MethodsAn individual-patient data meta-analysis of four multicentre randomized trials of EVAR versus open repair was conducted to a prespecified analysis plan, reporting on mortality, aneurysm-related mortality and reintervention.ResultsThe analysis included 2783 patients, with 14 245 person-years of follow-up (median 5·5 years). Early (0-6 months after randomization) mortality was lower in the EVAR groups (46 of 1393 versus 73 of 1390 deaths; pooled hazard ratio 0·61, 95 per cent c.i. 0·42 to 0·89; P = 0·010), primarily because 30-day operative mortality was lower in the EVAR groups (16 deaths versus 40 for open repair; pooled odds ratio 0·40, 95 per cent c.i. 0·22 to 0·74). Later (within 3 years) the survival curves converged, remaining converged to 8 years. Beyond 3 years, aneurysm-related mortality was significantly higher in the EVAR groups (19 deaths versus 3 for open repair; pooled hazard ratio 5·16, 1·49 to 17·89; P = 0·010). Patients with moderate renal dysfunction or previous coronary artery disease had no early survival advantage under EVAR. Those with peripheral artery disease had lower mortality under open repair (39 deaths versus 62 for EVAR; P = 0·022) in the period from 6 months to 4 years after randomization.ConclusionThe early survival advantage in the EVAR group, and its subsequent erosion, were confirmed. Over 5 years, patients of marginal fitness had no early survival advantage from EVAR compared with open repair. Aneurysm-related mortality and patients with low ankle : brachial pressure index contributed to the erosion of the early survival advantage for the EVAR group. Trial registration numbers: EVAR-1, ISRCTN55703451; DREAM (Dutch Randomized Endovascular Aneurysm Management), NCT00421330; ACE (Anévrysme de l'aorte abdominale, Chirurgie versus Endoprothèse), NCT00224718; OVER (Open Versus Endovascular Repair Trial for Abdominal Aortic Aneurysms), NCT00094575.

The article offers information of Storeria dekayi known as Dekay's Brownsnake has an extensive continental distribution from eastern Canada south into Central America.

One hundred and ninety-seven new chemical entities (NCEs) were investigated in man for the first time between 1964 and 1980 by the seven UK-owned pharmaceutical companies. Thirty-five of these NCEs have been marketed and 137 withdrawn from further research and development. There was an increase in the number of NCEs investigated each year, but this was counter-balanced by an increase in the number rejected. Development times increased from about 4.5 years in the 1960s to 9 years in the 1970s with an accompanying reduction in the effective patent life. [ABSTRACT FROM AUTHOR]

1. A total of six hundred and eighty three new chemical entities (NCEs), were marketed in the UK between 1960 and 1987. The number of NCEs introduced annually onto the UK market declined to an average of 20 per year in 1964 and subsequently to only 7 in 1985. 2. Average development times have increased fourfold since 1960 to a peak value of 13 years in 1984. The concomitant decline in effective patent life has resulted in a mean effective patent life of less than 10 years since the mid 1960s and no more than 6 years since the early 1980s, except for the cohort marketed in 1987. 3. The largest contribution to total development time was made by the clinical phase. For NCEs marketed in the mid 1960s it was 3.3 years increasing to a peak of almost 8 years in the early 1980s, and representing on average two-thirds of research and development time. 4. Between 1960 and the early 1970s total development time for central nervous system (CNS) agents, cardiovascular products and anti-infectives had doubled to 9, 8 and 7.3 years respectively. By the 1980s it was averaging 13 years for CNS agents and was 54% and 28% longer than for anti-infectives and cardiovascular compounds respectively. [ABSTRACT FROM AUTHOR]

1 A total of three hundred and nineteen new chemical entities (NCEs) were investigated in man for the first time between 1964 and 1985 by seven UK-owned pharmaceutical companies. The majority (96.2%), were self-originated by the UK company or one of its overseas subsidiaries. 2 There was an increase in the number of NCEs investigated each year in man, doubling from an average of 12 per year up to 1980, to over 20 per year between 1981 and 1985. The majority of first drug evaluations in human volunteers were carried out in the UK (92.2%), in contrast to evaluation of new medicines in patients, where 42.9% were first tested outside the UK. 3 The majority of NCEs evaluated in man (78%), were in four therapeutic classes: anti-infectives (32%), anti-allergics (22%), drugs acting on the central nervous system (13%) and cardiovascular system agents (11%). 4 By the end of 1985, 49 (15.4%) of these NCEs had been marketed in the UK and 198 (62.0%) discontinued from further development. The main reasons for termination were inappropriate pharmacokinetics in man (39.4%), and lack of clinical efficacy (29.3%). 5 Average development times increased from less than 2 years between 1964 and 1965, to around 8 years in the 1980s with a consequent reduction in the effective patent life. [ABSTRACT FROM AUTHOR]

Our sense of taste is critical for regulating food consumption. The fruit fly Drosophila represents a highly tractable model to investigate mechanisms of taste processing, but taste circuits beyond sensory neurons are largely unidentified. Here, we use a whole-brain connectome to investigate the organization of Drosophila taste circuits. We trace pathways from four populations of sensory neurons that detect different taste modalities and project to the subesophageal zone (SEZ). We find that second-order taste neurons are primarily located within the SEZ and largely segregated by taste modality, whereas third-order neurons have more projections outside the SEZ and more overlap between modalities. Taste projections out of the SEZ innervate regions implicated in feeding, olfactory processing, and learning. We characterize interconnections between taste pathways, identify modality-dependent differences in taste neuron properties, and use computational simulations to relate connectivity to predicted activity. These studies provide insight into the architecture of Drosophila taste circuits., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

While the extracellular matrix (ECM) has long been recognized for its structural contributions, anchoring cells for adhesion, providing mechanical support, and maintaining tissue integrity, recent efforts have elucidated its dynamic, reciprocal, and diverse properties on angiogenesis. The ECM modulates angiogenic signaling and mechanical transduction, influences the extent and degree of receptor activation, controls cellular behaviors, and serves as a reservoir for bioactive macromolecules. Collectively, these factors guide the formation, maturation, and stabilization of a functional vascular network. This review aims to shed light on the versatile roles of the ECM in angiogenesis, transcending its traditional functions as a mere structural material. We will explore its engagement and synergy in signaling modulation, interactions with various angiogenic factors, and highlight its importance in both health and disease. By capturing the essence of the ECM's diverse functionalities, we highlight the significance in the broader context of vascular biology, enabling the design of novel biomaterials to engineer vascularized tissues and their potential therapeutic implications., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer., Competing Interests: Declaration of interests S.S., T.A.P., C.Y.C., S.U., J.P., J.C., A.R., N.N., S.G., E.J., O.B., S.K., H.W., Z.W., Y.Z., K.T., L.C., A.M., J.L., P.P.K., S.S., P.F.R., E.C.G., S.Y., R.J., K.A.M., P.B., and H.L. are/were employees of Pfizer and some of the authors are shareholders in Pfizer Inc. L.C. and A.M. are co-inventors on patent WO2022013369. P.S., H.R.L., B.J.M., R.F., C.H., M.C., Y.B., and S.W. are inventors on patent WO2019243491 and have received payments from Monash University derived from distribution of licensing income received from Pfizer. P.P.K., S.S., P.F.R., Y.B., and P.S. are inventors on patent WO2020254946. P.S. is an inventor on patent WO2022013369. T.T., H.R.L and A.K.V. are inventors on patent WO2016198507 A1. The Thomas and Voss laboratories received research funding from the Cooperative Research Centre (CRC) for Cancer Therapeutics (CTx), Australia. T.T. and A.K.V. have received payments from a distribution of the licensing income from Pfizer for serving on an advisory board meeting for Pfizer. M.A.D. has been a member of advisory boards for CTX CRC, GSK, Storm Therapeutics, Celgene and Cambridge Epigenetix. S.-J.D. has been a member of advisory boards for Adela. M.A.D. and S.-J.D. receive research funding from CTx CRC and from the Pfizer Emerging Science Fund. Ian Street is a member of the Scientific Advisory Board of Oncology One Pty Ltd and has received payments from distribution of licensing income from Pfizer. J.N. is currently an adjunct professor at the University of New South Wales, Kensington, NSW, Australia. M.J.D and D.D.B. are currently working at South Australian immunoGENomics Cancer Institute (SAiGENCI), Faculty of Health and Medical Sciences, The University of Adelaide. J.C. is a current employee of oNKo-innate Pty Ltd. J.L. is currently an employee and shareholder of Belharra Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The Gulf Centralised Committee for Drug Registration (GCC-DR), as part of the Gulf Health Council (GHC), enables the consolidated registration of pharmaceutical products throughout the member states of the Gulf Cooperation Council., Objectives: The objectives of this study were to provide an update of the performance of the GCC-DR centralised procedure; evaluate the review times for new products submitted to the GCC Centralised Registration between January 2015 and December 2020; assess the impact of applying facilitated regulatory pathways and implementing a reliance strategy; identify the strengths and weaknesses of the centralised review process; and propose strategies that could enhance the GCC regulatory review process leading to improved access to medicines for patients., Methods: A standardised data collection template enabled the structured documentation of information collected by the Senior Regulatory Affairs and Regulatory Affairs Specialists from the Executive Board of the Health Ministers Council for GCC States to determine the GHC structure, resources, review models and milestones and timelines. The total number of applications approved was provided together with the average yearly timelines for new active substances and generics from January 2015 to December 2020 including both scientific assessment time from the agency as well as applicant response time to questions raised. Actual approval times for each product were calculated from the date of submission to the date of approval., Results: The fewest (58) new products were approved in 2019 and the most (200) in 2020. The average review times for new medicines were the longest (838 calendar days) in 2015 and the shortest (321 calendar days) in 2019. Important changes recently implemented include an increase in the number of GCC-DR meetings, adoption of a standardised electronic common technical document and GCC regulatory review template, removal of authorisation dependence on pricing agreements and introduction of a reliance strategy. Additional recommendations include Executive Committee mandates for dossier review, target times for dossier validation, scientific review and Expert Committee recommendation and training for quality decision making., Conclusions: GCC procedures and decision-making processes have been positively influenced by a variety of expert reviewers, unified guidelines and the implementation of a reliance strategy. Certain barriers must still be overcome to enhance the quality of the review, and to shorten regulatory review times without compromising the scientific robustness of the review., (© 2022. The Author(s).)

The COVID-19 pandemic has profoundly influenced the practice of medicine in Australia over the last 24 months. Recently, the development of several vaccines to COVID-19 has been accompanied by reports of an associated rare syndrome of thrombosis and thrombocytopaenia (VITTS). The possibility of this rare disorder confronts all clinicians who deal with acute thrombosis, particularly given the prevalence of patients who have recently been immunised. However, VITTS remains rare, and we believe unnecessary focus on its potential diagnosis may distract from other more common causes of acute thrombosis. We discuss this with reference to a recent case at our institution.

Covering: from 1938 up to March 2021The electron-rich indole side chain of tryptophan is a versatile substrate for peptide modification. Upon the action of various cyclases, the tryptophan side chain may be linked to a nearby amino acid residue, opening the door to a diverse range of cyclic peptide natural products. These compounds exhibit a wide array of biological activity and possess fascinating molecular architectures, which have made them popular targets for total synthesis studies. This review examines the isolation and bioactivity of tryptophan-linked cyclic peptide natural products, along with a discussion of their first total synthesis, and biosynthesis where this has been studied.

Cancer is often characterized by aberrant gene expression patterns caused by the inappropriate activation of transcription factors. Signal transducer and activator of transcription 3 (STAT3) is a key transcriptional regulator of many protumorigenic processes and is persistently activated in many types of human cancer. However, like many transcription factors, STAT3 has proven difficult to target clinically. To address this unmet clinical need, we previously developed a cell-based assay of STAT3 transcriptional activity and performed an unbiased and high-throughput screen of small molecules known to be biologically active in humans. We identified the antimicrobial drug pyrimethamine as a novel and specific inhibitor of STAT3 transcriptional activity. Here, we show that pyrimethamine does not significantly affect STAT3 phosphorylation, nuclear translocation, or DNA binding at concentrations sufficient to inhibit STAT3 transcriptional activity, suggesting a potentially novel mechanism of inhibition. To identify the direct molecular target of pyrimethamine and further elucidate the mechanism of action, we used a new quantitative proteome profiling approach called proteome integral solubility alteration coupled with a metabolomic analysis. We identified human dihydrofolate reductase as a target of pyrimethamine and demonstrated that the STAT3-inhibitory effects of pyrimethamine are the result of a deficiency in reduced folate downstream of dihydrofolate reductase inhibition, implicating folate metabolism in the regulation of STAT3 transcriptional activity. This study reveals a previously unknown regulatory node of the STAT3 pathway that may be important for the development of novel strategies to treat STAT3-driven cancers., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis. There is increasing interest in targeting chromatin regulatory pathways in difficult-to-treat cancers. In preliminary studies, we found that KDM4A (lysine-specific histone demethylase 4) was overexpressed in MPM., Methods: KDM4A protein expression was determined by immunohistochemistry or immunoblotting. Functional inhibition of KDM4A by targeted knockdown and small molecule drugs was correlated to cell growth using cell lines and a xenograft mouse model. Gene expression profiling was performed to identify KDM4A-dependent signature pathways., Results: Levels of KDM4A were found to be significantly elevated in MPM patients compared to normal mesothelial tissue. Inhibiting the enzyme activity efficiently reduced cell growth in vitro and reduced tumour growth in vivo. KDM4A inhibitor-induced apoptosis was further enhanced by the BH3 mimetic navitoclax. KDM4A expression was associated with pathways involved in cell growth and DNA repair. Interestingly, inhibitors of the DNA damage and replication checkpoint regulators CHK1 (prexasertib) and WEE1 (adavosertib) within the DNA double-strand break repair pathway, cooperated in the inhibition of cell growth., Conclusions: The results establish a novel and essential role for KDM4A in growth in preclinical models of MPM and identify potential therapeutic approaches to target KDM4A-dependent vulnerabilities., (© 2021. The Author(s).)

Background: Ataxia Telangiectasia Mutated (ATM) serine/threonine protein kinase is a known tumor suppressor, involved in DNA damage repair. It has prognostic and predictive therapeutic implications and is associated with aggressive prostate cancer (PCa)., Objective: To investigate the prognostic value of ATM protein expression in PCa patients and assessed the combined value of ATM, ERG, and PTEN status., Design Setting and Participants: This study consisted of 303 patients with incidental, locally advanced, and castrate-resistant PCa by transurethral resection of the prostate (TURP)., Outcome Measurements and Statistical Analysis: TURP samples from 303 PCa patients were assessed by immunohistochemistry (IHC for ATM, ERG, and PTEN. Individual and combined marker status were correlated with International Society of Urological Pathology Gleason grade group, overall survival (OS), and PCa-specific mortality (PCSM)., Results and Limitations: Decreased ATM expression (negative/weak intensity) occurred in 164/303 (54.1%) patients, and was associated with shorter OS and higher PCSM ( p  = 0.015 and p  = 0.001, respectively). Negative/weak ATM expression was significantly associated with PCSM with a hazard ratio of 2.09 (95% confidence interval 1.34-3.27, p  = 0.001). Assessment of Combined ATM/PTEN expression showed improved prognostic power to predict OS and PCSM, independent of Gleason grade groups., Conclusions: Decreased ATM protein expression is associated with poor outcomes in advanced PCa patients. Patients with combined low ATM/PTEN negative expression are at the highest risk for reduced OS and PCSM. Assessing the combined status of ATM/PTEN by IHC in PCa patients may aid in risk stratification relative to OS and PCSM. Moreover, since ATM plays an integral role in DNA damage response pathways, future studies will enhance our understanding of how outcomes of patients with altered ATM and PTEN expression can be improved further with poly-ADP ribose polymerase inhibitors (PARPi), combinations of PARPi and androgen receptor-targeted therapies, as well as platinum-based chemotherapies., Patient Summary: Lower ATM intensity is associated with increased cancer-specific mortality in prostate cancer patients. Patients with lower ATM and PTEN negative expression showed decreased overall survival and increased cancer mortality compared with controls., (© 2021 The Author(s).)

Background: Data from multiple surgical studies and settings have reported an increase in adverse events in patients admitted or treated on weekends. The aim of this study was to investigate short-term outcomes for patients undergoing carotid endarterectomy (CEA) in Australia and New Zealand based on the day of surgery., Methods: This is a retrospective observational cohort study. Analysis of 7,857 CEAs recorded for more than 4 years in the Australasian Vascular Audit database was performed. Multivariate logistic regression was used to compare the following outcomes between CEAs performed during the week and on the weekend: (1) in-hospital stroke and/or death; (2) other postoperative complications; and (3) shorter (2 days or less) length of stay (LOS)., Results: A total of 7,857 CEAs were recorded, with significantly more procedures performed during the week (n = 7,333, P < 0.001). There was no statistically significant difference in the frequency of stroke and/or death or other complications between CEAs performed during the week or on the weekend (P = 0.294 and P = 0.806, respectively). However, there was a significant difference in LOS for procedures performed during the weekend, with more of these patients being discharged within 2 days compared with procedures performed during the week (56.8% vs. 51.5%; P = 0.003). Multivariable logistic regression found no effect of day of the week on the odds of postoperative stroke and/or death (P = 0.685). Day of surgery was also not associated with greater odds of other complications (P = 0.925). However, CEAs performed by nonconsultants had significantly lower adjusted odds of other complications (3.1% vs. 4.1%; P = 0.033). The adjusted odds of having a shorter LOS were significantly greater for operations taking place on the weekend (P = 0.003)., Conclusions: In Australia and New Zealand, there appears to be no disadvantage to performing CEA on the weekend, in terms of stroke and/or death. Level of experience of the primary operator does not affect rates of stroke and/or death after CEA. Weekend CEA is associated with a shorter hospital LOS., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim: Waldenström macroglobulinemia (WM) is a low-grade B-cell lymphoma characterized by overproduction of monoclonal IgM. To date, there are no therapies that provide a cure for WM patients, and therefore, it is important to explore new therapies. Little is known about the efficiency of epigenetic targeting in WM. Materials & methods: WM cells were treated with BET inhibitors (JQ1 and I-BET-762) and venetoclax, panobinostat or ibrutinib. Results: BET inhibition reduces growth of WM cells, with little effect on survival. This finding was enhanced by combination therapy, with panobinostat (LBH589) showing the highest synergy. Conclusion: Our studies identify BET inhibitors as effective therapy for WM, and these inhibitors can be enhanced in combination with BCL2 or histone deacetylase inhibition.

Background: Pharmaceutical companies and regulatory agencies endeavor to relate their decision making with outcomes to improve future decision making and to ensure that gained knowledge is fed back into a learning system. Nevertheless, such a correlation can only be achieved by documenting the expected outcome of a decision at the time it is made, enabling comparison of the expected outcome with the actual result., Methods: Participants at an international workshop discussed how the documentation of decisions could be evolved as companies and agencies look to improve their knowledge base. Discussions were informed by a pre-workshop survey of pharmaceutical companies and regulatory agencies., Results: Most survey participants from 12 companies (55% response rate) and 11 agencies (73% response) have a system in place to enable documentation of major decisions, however, systems are used primarily to document outcomes rather than the process, while information from documentation is not always used, and feedback loops are not in place. The majority of participants indicated that their organization currently documents most decision-making practices included in the proposed template. Workshop participants agreed that all major past decisions should be referenceable and suggested incentives to enable decisions to be referenced, and confirmed elements and characteristics of a decision-documentation template., Conclusions: This survey and workshop identified the current landscape and gaps in the documentation of decision making and suggested revisions for a proposed documentation template. The use of technology to enable information extraction with support from artificial intelligence and future decision making was a recommendation highlighted by participants.

Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis 1 . To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We found that the previously described immunoreactive and mesenchymal subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells 2 . Malignant cell variability was partly explained by heterogeneous copy number alteration patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in single-cell RNA sequencing of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient ascites-derived xenograft models. Inhibition of the JAK/STAT pathway, which was expressed in both malignant cells and cancer-associated fibroblasts, had potent anti-tumor activity in primary short-term cultures and patient-derived xenograft models. Our work contributes to resolving the HSGOC landscape 3-5 and provides a resource for the development of novel therapeutic approaches.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background: Endometriosis is complex, but identifying the novel biomarkers, inflammatory molecules, and genetic links holds the key to the enhanced detection, prediction and treatment of both endometriosis and endometriosis related malignant neoplasia. Here we review the literature relating to the specific molecular mechanism(s) mediating tumorigenesis arising within endometriosis., Methods: Guidance (e.g. Cochrane) and published studies were identified. The Published studies were identified through PubMed using the systematic review methods filter, and the authors' topic knowledge. These data were reviewed to identify key and relevant articles to create a comprehensive review article to explore the molecular fingerprint associated with in endometriosis-driven tumorigenesis., Results: An important focus is the link between C3aR1, PGR, ER1, SOX-17 and other relevant gene expression profiles and endometriosis-driven tumorigenesis. Further studies should also focus on the combined use of CA-125 with HE-4, and the role for OVA1/MIA as clinically relevant diagnostic biomarkers in the prediction of endometriosis-driven tumorigenesis., Conclusions: Elucidating endometriosis' molecular fingerprint is to understand the molecular mechanisms that drive the endometriosis-associated malignant phenotype. A better understanding of the predictive roles of these genes and the value of the biomarker proteins will allow for the derivation of unique molecular treatment algorithms to better serve our patients., Competing Interests: Conflicts of Interest: The authors declare no conflicts of interest.

Background: To evaluate the quality of the decision-making processes of pharmaceutical companies during medicines development for evidence generation to support reimbursement of new medicines and the appraisal recommendation decision-making process by health technology assessment (HTA) agencies., Methods: Two questionnaires were developed and subsequently piloted for the purpose of content validation. These were sent to 24 pharmaceutical companies and 16 HTA agencies., Results: Responses were obtained from 11 companies and 11 HTA agencies. Some similarities were identified between the decision-making processes of companies and agencies, such as the use of committees, having a primarily mixed (qualitative/quantitative) internal decisionmaking system, as well as the lack of systematic assessments of quality decision making and the relatively infrequent use of formal decision-making frameworks. Nevertheless, the results indicate differences as companies and agencies use diverse processes to arrive at the final decision either through consensus, majority vote, or an individual making the decision. The majority of companies and agencies believe that the quality of decision making can and should be measured. Moreover, organizations considered the occurrence of biases within their organization as pertinent. Finally, almost all the participants felt that there was room for improvement for their organization's quality of decision making., Conclusion: These findings are consistent with a published study on regulatory processes and support the need for more consistent and predictable decision-making processes during the life cycle of medicines. This could be achieved through capacity building, systematically evaluating the quality of decision making, and encouraging utilization of formal decision-making frameworks within companies and agencies.

The transcription factor STAT3 regulates genes governing critical cellular processes such as proliferation, survival, and self-renewal. While STAT3 transcriptional function is activated rapidly and transiently in response to physiologic signals, through a variety of mechanisms it can become constitutively activated in the pathogenesis of cancer. This leads to chronic expression of genes that underlie malignant cellular behavior. However, STAT3 is known to interact with other proteins, which may modulate its function. Understanding these interactions can provide insights into novel aspects of STAT3 function and may also suggest strategies to therapeutically target the large number of cancers driven by constitutively activated STAT3. To identify critical modulators of STAT3 transcriptional function, we performed an RNA-interference based screen in a cell-based system that allows quantitative measurement of STAT3 activity. From this approach, we identified CDK5 kinase regulatory-subunit associated protein 3 (CDK5RAP3) as an enhancer of STAT3-dependent gene expression. We found that STAT3 transcriptional function is modulated by CDK5RAP3 in cancer cells, and silencing CDK5RAP3 reduces STAT3-mediated tumorigenic phenotypes including clonogenesis and migration. Mechanistically, CDK5RAP3 binds to STAT3-regulated genomic loci, in a STAT3-dependent manner. In primary human breast cancers, the expression of CDK5RAP3 expression was associated with STAT3 gene expression signatures as well as the expression of individual STAT3 target genes. These findings reveal a novel aspect of STAT3 transcriptional function and potentially provide both a biomarker of enhanced STAT3-dependent gene expression as well as a unique mechanism to therapeutically target STAT3., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Atovaquone, a US Food and Drug Administration-approved antiparasitic drug previously shown to reduce interleukin-6/STAT3 signaling in myeloma cells, is well tolerated, and plasma concentrations of 40 to 80 µM have been achieved with pediatric and adult dosing. We conducted preclinical testing of atovaquone with acute myeloid leukemia (AML) cell lines and pediatric patient samples. Atovaquone induced apoptosis with an EC50 <30 µM for most AML lines and primary pediatric AML specimens. In NSG mice xenografted with luciferase-expressing THP-1 cells and in those receiving a patient-derived xenograft, atovaquone-treated mice demonstrated decreased disease burden and prolonged survival. To gain a better understanding of the mechanism of atovaquone, we performed an integrated analysis of gene expression changes occurring in cancer cell lines after atovaquone exposure. Atovaquone promoted phosphorylation of eIF2α, a key component of the integrated stress response and master regulator of protein translation. Increased levels of phosphorylated eIF2α led to greater abundance of the transcription factor ATF4 and its target genes, including proapoptotic CHOP and CHAC1. Furthermore, atovaquone upregulated REDD1, an ATF4 target gene and negative regulator of the mechanistic target of rapamycin (mTOR), and caused REDD1-mediated inhibition of mTOR activity with similar efficacy as rapamycin. Additionally, atovaquone suppressed the oxygen consumption rate of AML cells, which has specific implications for chemotherapy-resistant AML blasts that rely on oxidative phosphorylation for survival. Our results provide insight into the complex biological effects of atovaquone, highlighting its potential as an anticancer therapy with novel and diverse mechanisms of action, and support further clinical evaluation of atovaquone for pediatric and adult AML., (© 2019 by The American Society of Hematology.)