Patient and carer transition outcomes and experiences at the Westmead Centre for Adolescent and Young Adult Health, Westmead, Australia: protocol for a longitudinal cohort study.

INTRODUCTION: The Westmead Centre for Adolescent and Young Adult Health is a purpose-built facility supporting integrated care for young patients with a variety of long-term health conditions transitioning from paediatric services at the Children's Hospital at Westmead to adult services at Westmead Hospital, Australia. METHODS AND ANALYSIS: This protocol outlines a prospective, within-subjects, repeated-measures longitudinal cohort study to measure self-reported experiences and outcomes of patients (12-25 years) and carers accessing transition care at the Centre for Adolescent and Young Adult Health. Longitudinal self-report data will be collected using Research Electronic Data Capture surveys at the date of service entry (recruitment baseline), with follow-ups occurring at 6 months, 12 months, 18 months and after transfer to adult services. Surveys include validated demographic, general health and psychosocial questionnaires. Participant survey responses will be linked to routinely recorded data from hospital medical records. Hospital medical records data will be extracted for the 12 months prior to service entry up to 18 months post service entry. All young people accessing services at the Centre for Adolescent and Young Adult Health that meet inclusion criteria will be invited to join the study with research processes to be embedded into routine practices at the site. We expect a sample of approximately 225 patients with a minimum sample of 65 paired responses required to examine pre-post changes in patient distress. Data analysis will include standard descriptive statistics and paired-sample tests. Regression models and Kaplan-Meier method for time-to-event outcomes will be used to analyse data once sample size and test requirements are satisfied. ETHICS AND DISSEMINATION: The study has ethics approval through the Sydney Children's Hospitals Network Human Research Ethics Committee (2021/ETH11125) and site-specific approvals from the Western Sydney Local Health District (2021/STE03184) and the Sydney Children's Hospitals Network (2039/STE00977). Patients under the age of 18 will require parental/carer consent to participate in the study. Patients over 18 years can provide informed consent for their participation in the research. Dissemination of research will occur through publication of peer-reviewed journal reports and conference presentations using aggregated data that precludes the identification of individuals. Through this work, we hope to develop a digital common that can be shared with other researchers and clinicians wanting to develop a standardised and shared approach to the measurement of patient outcomes and experiences in transition care.

Prediction of the mechanism of suicide among Minnesota residents using data from the Minnesota violent death reporting system (MNVDRS).

BACKGROUND: Suicide remains a major public health problem, and firearms are used in approximately half of all such incidents. This study sought to predict the occurrence of suicide specifically by firearm, as opposed to any other means of suicide, in order to help inform possible life-saving interventions. METHODS: This study involved data from the Minnesota Violent Death Reporting System. Models evaluated whether data beyond basic demographics generated increased prediction accuracy. Models were built using random forests, logistic regression and data imputation. Models were evaluated for prediction accuracy using the area under the curve analysis and for proper calibration. RESULTS: Results showed that models constructed with social determinants and personal history data led to increased prediction accuracy in comparison to models constructed with basic demographic information only. The study identified an optimised 'top 20' variables model with a 73% chance of correctly discerning relative incident risk for a pair of individuals. Age, height/weight, employment industry/occupation, sex and education level were found to be most highly predictive of firearm suicide in the study's 'top 20' model. CONCLUSIONS: The study demonstrated that the use of a firearm in a death by suicide, as opposed to any other means of suicide, can be reasonably well predicted when an individual's social determinants and personal history are considered. These predictive models could help inform many prevention strategies, such as safe storage practices, background checks for firearm purchases or red flag laws.

Development and implementation of Australian State, territory, and national policy on the health and wellbeing of adolescents and young adults: An exploration of policy actor perspectives using the Consolidated Framework for Implementation Research.

OBJECTIVES: Government policies that support the health and wellbeing of young people (aged 10 to 25) can have important individual and societal impacts. The aim of this study was to explore policy actor perspectives on the development and implementation of Australian government policies focussed on the health and wellbeing of young people. METHODS: We utilised a qualitative research design consisting of semi-structured interviews with policy actors with experience working with Australian youth health policies. Our interview guide and analyses were informed by the Consolidated Framework for Implementation Research (CFIR). We interviewed 19 participants from various national, state, and territory bodies. RESULTS: Several specific barriers and facilitators to policy development and implementation were identified using the Consolidated Framework for Implementation Research. Key policy development barriers were limited available resources (e.g. staffing and funding) and low relative priority within health and political systems. Key policy implementation barriers were limited available resources, limited policy compatibility with health services, cosmopolitanism issues related to interagency collaboration, and a lack of policy evaluation. Meaningful engagement of young people could also be improved. CONCLUSIONS: Although Australian youth health policies are perceived as evidence-based and comprehensively developed, the ability to promote implementation remains stalled. IMPLICATIONS FOR PUBLIC HEALTH: The development of policy implementation plans, monitoring and evaluation mechanisms, funding and resources, and a strong commitment to removing barriers to working across multiple departments and systems is required to improve outcomes for young people.

Discovery and Evaluation of C6-Substituted Pyrazolopyrimidine-Based Bisphosphonate Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase and Evaluation of Their Antitumor Efficacy in Multiple Myeloma, Pancreatic Ductal Adenocarcinoma, and Colorectal Cancer.

Novel C6-substituted pyrazolo[3,4-d]pyrimidine- and C2-substituted purine-based bisphosphonate (C6-PyraP-BP and C2-Pur-BP, respectively) inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS) were designed and evaluated for their ability to block the proliferation of multiple myeloma (MM), pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC) cells. Pyrazolo[3,4-d]pyrimidine analogs were identified that induce selective intracellular target engagement leading to apoptosis and downregulate the prenylation of Rap-1A in MM, PDAC, and CRC cells. The C6-PyraP-BP inhibitor RB-07-16 was found to exhibit antitumor efficacy in xenograft mouse models of MM and PDAC, significantly reducing tumor growth without substantially increasing liver enzymes or causing significant histopathologic damage, usually associated with hepatotoxicity. RB-07-16 is a metabolically stable compound in cross-species liver microsomes, does not inhibit key CYP 450 enzymes, and exhibits good systemic circulation in rat. Collectively, the current studies provide encouraging support for further optimization of the pyrazolo[3,4-d]pyrimidine-based GGPPS inhibitors as potential human therapeutics for various cancers.

Umami taste perception and preferences of the domestic cat (Felis catus), an obligate carnivore.

The domestic cat (Felis catus) is an obligate carnivore, and as such has a meat-based diet. Several studies on the taste perception of cats have been reported, indicating that their sense of taste has evolved based on their carnivorous diet. Here, we propose that umami (mediated by Tas1r1-Tas1r3) is the main appetitive taste modality for the domestic cat by characterizing the umami taste of a range of nucleotides, amino acids, and their mixtures for cats obtained using complementary methods. We show for the first time that cats express Tas1r1 in taste papillae. The cat umami receptor responds to a range of nucleotides as agonists, with the purine nucleotides having the highest activity. Their umami receptor does not respond to any amino acids alone; however, 11 l-amino acids with a range of chemical characteristics act as enhancers in combination with a nucleotide. l-Glutamic acid and l-Aspartic acid are not active as either agonists or enhancers of the cat umami receptor due to changes in key binding residues at positions 170 and 302. Overall, cats have an appetitive behavioral response for nucleotides, l-amino acids, and their mixtures. We postulate that the renowned palatability of tuna for cats may be due, at least in part, to its specific combination of high levels of inosine monophosphate and free l-Histidine that produces a strong synergistic umami taste enhancement. These results demonstrate the critical role that the umami receptor plays in enabling cats to detect key taste compounds present in meat.

Psychosocial assessment of adolescents and young adults in paediatric hospital settings: patient and staff perspectives on implementation of the e-HEEADSSS.

BACKGROUND: The main causes of morbidity and mortality for adolescents and young adults are preventable and stem from psychosocial and behavioural concerns. Psychosocial assessments can help clinicians to identify and respond holistically to risks and strengths that may impact upon a young person's physical and mental health. Despite broad support at a policy level, the implementation of routine psychosocial screening for young people remains varied in Australian health settings. The current study focused on the pilot implementation of a digital patient-completed psychosocial assessment (the e-HEEADSSS) at the Sydney Children's Hospital Network. The aim of this research was to evaluate patient and staff barriers and facilitators to local implementation. METHODS: The research used a qualitative descriptive research design. Semi-structured interviews were conducted online with 8 young patients and 8 staff members who had completed or actioned an e-HEEADSSS assessment within the prior 5 weeks. Qualitative coding of interview transcripts was carried out in NVivo 12. The Consolidated Framework for Implementation Research guided the interview framework and qualitative analyses. RESULTS: Results demonstrated strong support for the e-HEEADSSS from patients and staff. Key reported facilitators included strong design and functionality, reduced time requirements, greater convenience, improved disclosure, adaptability across settings, greater perceived privacy, improved fidelity, and reduced stigma for young people. The key barriers were related to concerns over available resources, the sustainability and continuity of staff training, perceived availability of clinical pathways for follow-up and referrals, and risks related to off-site completions. Clinicians need to adequately explain the e-HEEADSSS assessment to patients, educate them about it, and make sure that they receive timely feedback on the results. Greater reassurance and education regarding the rigour of confidentiality and data handling procedures is required for patients and staff. CONCLUSIONS: Our findings indicate that continued work is required to support the integration and sustainability of digital psychosocial assessments for young people at the Sydney Children's Hospital Network. The e-HEEADSSS shows promise as an implementable intervention to achieve this goal. Further research is required to determine the scalability of this intervention across the broader health system.

Bitter taste sensitivity in domestic dogs (Canis familiaris) and its relevance to bitter deterrents of ingestion.

As the most favoured animal companion of humans, dogs occupy a unique place in society. Understanding the senses of the dog can bring benefits to both the dogs themselves and their owners. In the case of bitter taste, research may provide useful information on sensitivity to, and acceptance of, diets containing bitter tasting materials. It may also help to protect dogs from the accidental ingestion of toxic substances, as in some instances bitter tasting additives are used as deterrents to ingestion. In this study we examined the receptive range of dog bitter taste receptors (Tas2rs). We found that orthologous dog and human receptors do not always share the same receptive ranges using in vitro assays. One bitter chemical often used as a deterrent, denatonium benzoate, is only moderately active against dTas2r4, and is almost completely inactive against other dog Tas2rs, including dTas2r10, a highly sensitive receptor in humans. We substituted amino acids to create chimeric dog-human versions of the Tas2r10 receptor and found the ECL2 region partly determined denatonium sensitivity. We further confirmed the reduced sensitivity of dogs to this compound in vivo. A concentration of 100µM (44.7ppm) denatonium benzoate was effective as a deterrent to dog ingestion in a two-bottle choice test indicating higher concentrations may increase efficacy for dogs. These data can inform the choice and concentration of bitter deterrents added to toxic substances to help reduce the occurrence of accidental dog poisonings.

Long-term daily feeding of cannabidiol is well-tolerated by healthy dogs.

Cannabidiol (CBD) containing dog food and treats are widely commercially available, mirroring the growing popularity of CBD as a supplement for humans. Despite this, experimental evidence of the safety and efficacy of long-term oral exposure in dogs is lacking. The purpose of this study was to address the gap in knowledge around the longer-term suitability and tolerance of a broad-spectrum CBD (THC-free) distillate in clinically healthy dogs. The study was a randomized, placebo-controlled, and blinded study where one group of twenty dogs received daily CBD capsules at a dose of 4 mg/kg of body weight (BW) for a period of 6 months. The control group of twenty dogs received placebo capsules. A comprehensive suite of physiological health measures was performed throughout the study at baseline, and after 2, 4, 10, 18, and 26 weeks of exposure, followed by 4 weeks of washout. CBD concentrations were measured at the same cadence in plasma, feces and urine. Health measures included biochemistry, hematology, urinalysis, in addition to fortnightly veterinary examinations, twice daily well-being observations, and a daily quality-of-life survey. Biochemistry and hematology showed no clinically significant alterations apart from a transient elevation in alkaline phosphatase (ALP) in just over half of the dogs receiving CBD. This elevation was observed in the absence of concurrent elevations of other liver parameters, and without any adverse effects on health and wellbeing. Furthermore, bone alkaline phosphatase (BALP) was simultaneously elevated with a significant, strong (r > 0.9) positive correlation between the two measures, suggesting that the elevation of total ALP was at least partly due to the bone-derived isoform. This study provides evidence that a once-daily oral dose of 4 mg CBD/kg BW is well tolerated in clinically healthy dogs for a duration of 6-months.

Implementation science in adolescent healthcare research: an integrative review.

BACKGROUND: Multiple theories, models and frameworks have been developed to assist implementation of evidence-based practice. However, to date there has been no review of implementation literature specific to adolescent healthcare. This integrative review therefore aimed to determine what implementation science theories, models and frameworks have been applied, what elements of these frameworks have been identified as influential in promoting the implementation and sustainability of service intervention, and to what extent, in what capacity and at what time points has the contribution of adolescent consumer perspectives on evidence implementation been considered.  METHODS: An integrative design was used and reported based on a modified form of the PRISMA (2020) checklist. Seven databases were searched for English language primary research which included any implementation science theory, model or framework developed for/with adolescents or applied in relation to adolescent healthcare services within the past 10 years. Content and thematic analysis were applied with the Consolidated Framework for Implementation Research (CFIR) used to frame analysis of the barriers and facilitators to effective implementation of evidence-informed interventions within youth health settings. RESULTS: From 8717 citations, 13 papers reporting 12 studies were retained. Nine different implementation science theories, frameworks or approaches were applied; six of 12 studies used the CFIR, solely or with other models. All CFIR domains were represented as facilitators and barriers for implementation in included studies. However, there was little or no inclusion of adolescents in the development or review of these initiatives. Only three mentioned youth input, occurring in the pre-implementation or implementation stages. CONCLUSIONS: The few studies found for this review highlight the internationally under-developed nature of this topic. Flagging the importance of the unique characteristics of this particular age group, and of the interventions and strategies to target it, the minimal input of adolescent consumers is cause for concern. Further research is clearly needed and must ensure that youth consumers are engaged from the start and consistently throughout; that their voice is prioritised and not tokenistic; that their contribution is taken seriously. Only then will age-appropriate evidence implementation enable innovations in youth health services to achieve the evidence-based outcomes they offer. TRIAL REGISTRATION: PROSPERO 2020 CRD42020201142 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=201142.

Building evidence into youth health policy: a case study of the Access 3 knowledge translation forum.

BACKGROUND: Effective integration of evidence and youth perspectives into policy is crucial for supporting the future health and well-being of young people. The aim of this project was to translate evidence from the Access 3 project to support development of a new state policy on youth health and well-being within New South Wales (NSW), Australia. Ensuring the active contribution of young people within policy development was a key objective of the knowledge translation (KT) process. METHODS: The KT activity consisted of a 1-day facilitated forum with 64 purposively sampled stakeholders. Participants included eight young people, 14 policy-makers, 15 academics, 22 clinicians or managers from NSW health services, four general practitioners and one mental health service worker. Research to be translated came from the synthesized findings of the NSW Access 3 project. The design of the forum included stakeholder presentations and group workshops, guided by the 2003 Lavis et al. KT framework that was improved by the Grimshaw et al. KT framework in 2012. Members of the Access 3 research team took on the role of knowledge brokers throughout the KT process. Participant satisfaction with the workshop was evaluated using a brief self-report survey. Policy uptake was determined through examination of the subsequent NSW Youth Health Framework 2017-2024. RESULTS: A total of 25 policy recommendations were established through the workshop, and these were grouped into six themes that broadly aligned with the synthesized findings from the Access 3 project. The six policy themes were (1) technology solutions, (2) integrated care and investment to build capacity, (3) adolescent health checks, (4) workforce, (5) youth participation and (6) youth health indicators. Forum members were asked to vote on the importance of individual recommendations. These policy recommendations were subsequently presented to the NSW Ministry of Health, with some evidence of policy uptake identified. The majority of participants rated the forum positively. CONCLUSIONS: The utilization of KT theories and active youth engagement led to the successful translation of research evidence and youth perspectives into NSW youth health policy. Future research should examine the implementation of policy arising from these KT efforts.

Synthesis and Evaluation of Structurally Diverse C-2-Substituted Thienopyrimidine-Based Inhibitors of the Human Geranylgeranyl Pyrophosphate Synthase.

Novel analogues of C-2-substituted thienopyrimidine-based bisphosphonates (C2-ThP-BPs) are described that are potent inhibitors of the human geranylgeranyl pyrophosphate synthase (hGGPPS). Members of this class of compounds induce target-selective apoptosis of multiple myeloma (MM) cells and exhibit antimyeloma activity in vivo. A key structural element of these inhibitors is a linker moiety that connects their (((2-phenylthieno[2,3-d]pyrimidin-4-yl)amino)methylene)bisphosphonic acid core to various side chains. The structural diversity of this linker moiety, as well as the side chains attached to it, was investigated and found to significantly impact the toxicity of these compounds in MM cells. The most potent inhibitor identified was evaluated in mouse and rat for liver toxicity and systemic exposure, respectively, providing further optimism for the potential value of such compounds as human therapeutics.

CLIC-01: Manufacture and distribution of non-cryopreserved CAR-T cells for patients with CD19 positive hematologic malignancies.

Access to commercial CD19 CAR-T cells remains limited even in wealthy countries like Canada due to clinical, logistical, and financial barriers related to centrally manufactured products. We created a non-commercial academic platform for end-to-end manufacturing of CAR-T cells within Canada's publicly funded healthcare system. We report initial results from a single-arm, open-label study to determine the safety and efficacy of in-house manufactured CD19 CAR-T cells (entitled CLIC-1901) in participants with relapsed/refractory CD19 positive hematologic malignancies. Using a GMP compliant semi-automated, closed process on the Miltenyi Prodigy, T cells were transduced with lentiviral vector bearing a 4-1BB anti-CD19 CAR transgene and expanded. Participants underwent lymphodepletion with fludarabine and cyclophosphamide, followed by infusion of non-cryopreserved CAR-T cells. Thirty participants with non-Hodgkin's lymphoma (n=25) or acute lymphoblastic leukemia (n=5) were infused with CLIC-1901: 21 males (70%), median age 66 (range 18-75). Time from enrollment to CLIC-1901 infusion was a median of 20 days (range 15-48). The median CLIC-1901 dose infused was 2.3 × 106 CAR-T cells/kg (range 0.13-3.6 × 106/kg). Toxicity included ≥ grade 3 cytokine release syndrome (n=2) and neurotoxicity (n=1). Median follow-up was 6.5 months. Overall response rate at day 28 was 76.7%. Median progression-free and overall survival was 6 months (95%CI 3-not estimable) and 11 months (95% 6.6-not estimable), respectively. This is the first trial of in-house manufactured CAR-T cells in Canada and demonstrates that administering fresh CLIC-1901 product is fast, safe, and efficacious. Our experience may provide helpful guidance for other jurisdictions seeking to create feasible and sustainable CAR-T cell programs in research-oriented yet resource-constrained settings. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03765177, identifier NCT03765177.

Longitudinal single-cell analysis of a myeloma mouse model identifies subclonal molecular programs associated with progression.

Molecular programs that underlie precursor progression in multiple myeloma are incompletely understood. Here, we report a disease spectrum-spanning, single-cell analysis of the Vκ*MYC myeloma mouse model. Using samples obtained from mice with serologically undetectable disease, we identify malignant cells as early as 30 weeks of age and show that these tumours contain subclonal copy number variations that persist throughout progression. We detect intratumoural heterogeneity driven by transcriptional variability during active disease and show that subclonal expression programs are enriched at different times throughout early disease. We then show how one subclonal program related to GCN2 stress response is progressively activated during progression in myeloma patients. Finally, we use chemical and genetic perturbation of GCN2 in vitro to support this pathway as a therapeutic target in myeloma. These findings therefore present a model of precursor progression in Vκ*MYC mice, nominate an adaptive mechanism important for myeloma survival, and highlight the need for single-cell analyses to understand the biological underpinnings of disease progression.

Australian federal, state and territory policy on the health and wellbeing of young people: A scoping review.

BACKGROUND: The health and wellbeing of young people are critical for the future of society but the extent to which they are addressed by overarching Australian Federal, State and Territory health policy is difficult to determine. Analysing high-level youth health policy will help establish how Australian governments are articulating and prioritising issues and may guide local and international health agendas. METHODS: This scoping review aimed to determine the extent, range and nature of Australian high-level government policy focused on the general health and wellbeing of the general population of young people. Policies published by Australian Federal, State, or Territory government departments between 2008 and 2019 were thematically analysed employing Braun and Clark's six-step recursive framework. FINDINGS: Twelve policy documents met inclusion criteria. Three meta-themes emerged, comprising policy development, youth health challenges, and policy goals. Policy goals fell into three ubiquitous and overarching categories focused on supporting public health, promoting equity, and improving the health system for young people. CONCLUSIONS: A number of youth-specific health policies have been developed by Australian governments in recent years. Whilst goals and strategies are clearly articulated, more can be done to ensure a youth voice in policy development. The policy goals of supporting public health, promoting equity and improving the health system deserve consideration from other countries developing youth health policies.

Nonparametric time series summary statistics for high-frequency accelerometry data from individuals with advanced dementia.

Accelerometry data has been widely used to measure activity and the circadian rhythm of individuals across the health sciences, in particular with people with advanced dementia. Modern accelerometers can record continuous observations on a single individual for several days at a sampling frequency of the order of one hertz. Such rich and lengthy data sets provide new opportunities for statistical insight, but also pose challenges in selecting from a wide range of possible summary statistics, and how the calculation of such statistics should be optimally tuned and implemented. In this paper, we build on existing approaches, as well as propose new summary statistics, and detail how these should be implemented with high frequency accelerometry data. We test and validate our methods on an observed data set from 26 recordings from individuals with advanced dementia and 14 recordings from individuals without dementia. We study four metrics: Interdaily stability (IS), intradaily variability (IV), the scaling exponent from detrended fluctuation analysis (DFA), and a novel nonparametric estimator which we call the proportion of variance (PoV), which calculates the strength of the circadian rhythm using spectral density estimation. We perform a detailed analysis indicating how the time series should be optimally subsampled to calculate IV, and recommend a subsampling rate of approximately 5 minutes for the dataset that has been studied. In addition, we propose the use of the DFA scaling exponent separately for daytime and nighttime, to further separate effects between individuals. We compare the relationships between all these methods and show that they effectively capture different features of the time series.

IL6 Promotes a STAT3-PRL3 Feedforward Loop via SHP2 Repression in Multiple Myeloma.

Overexpression of PRL-3, an oncogenic phosphatase, was identified as a novel cluster in patients with newly diagnosed multiple myeloma. However, the regulation and oncogenic activities of PRL-3 in multiple myeloma warrant further investigation. Here, we report that IL6 activates STAT3, which acts as a direct transcriptional regulator of PRL-3. Upregulation of PRL-3 increased myeloma cell viability and rephosphorylated STAT3 in a biphasic manner through direct interaction and deactivation of SHP2, thus blocking the gp130 (Y759)-mediated repression of STAT3 activity. Abrogation of PRL-3 reduced myeloma cell survival, clonogenicity, and tumorigenesis, and detailed mechanistic studies revealed "deactivation" of effector proteins such as Akt, Erk1/2, Src, STAT1, and STAT3. Furthermore, loss of PRL-3 efficiently abolished nuclear localization of STAT3 and reduced its occupancy on the promoter of target genes c-Myc and Mcl-1, and antiapoptotic genes Bcl2 and Bcl-xL. PRL-3 also played a role in the acquired resistance of myeloma cells to bortezomib, which could be overcome by PRL-3 silencing. Of clinical relevance, STAT3 and PRL-3 expression was positively correlated in five independent cohorts, and the STAT3 activation signature was significantly enriched in patients with high PRL-3 expression. Furthermore, PRL-3 could be used as a biomarker to identify high-risk patients with multiple myeloma that exhibited poor prognosis and inferior outcome even when treated with novel combinational therapeutics (proteasome inhibitors and immunomodulatory imide drugs). Conclusively, our results support a feedforward mechanism between STAT3 and PRL-3 that prolongs prosurvival signaling in multiple myeloma, and suggest targeting PRL-3 as a valid therapeutic opportunity in multiple myeloma. SIGNIFICANCE: IL6 promotes STAT3-dependent transcriptional upregulation of PRL-3, which in turn re-phosphorylates STAT3 and aberrantly activates STAT3 target genes, leading to bortezomib resistance in multiple myeloma.

Inhibition of farnesyl pyrophosphate (FPP) and/or geranylgeranyl pyrophosphate (GGPP) biosynthesis and its implication in the treatment of cancers.

Dysregulation of isoprenoid biosynthesis is implicated in numerous biochemical disorders that play a role in the onset and/or progression of age-related diseases, such as hypercholesterolemia, osteoporosis, various cancers, and neurodegeneration. The mevalonate metabolic pathway is responsible for the biosynthesis of the two key isoprenoid metabolites, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Post-translational prenylation of various proteins, including the small GTP-binding proteins (GTPases), with either FPP or GGPP is vital for proper localization and activation of these proteins. Prenylated GTPases play a critical role in cell signaling, proliferation, cellular plasticity, oncogenesis, and cancer metastasis. Pre-clinical and clinical studies strongly suggest that inhibition of protein prenylation can be an effective treatment for non-skeletal cancers. In this review, we summarize the most recent drug discovery efforts focusing on blocking protein farnesylation and/or geranylgeranylation and the biochemical and structural data available in guiding the current on-going studies in drug discovery. Furthermore, we provide a summary on the biochemical association between disruption of protein prenylation, endoplasmic reticulum (ER) stress, unfolded protein response (UPR) signaling, and cancer.

Oxo-aglaiastatin-Mediated Inhibition of Translation Initiation.

Translation is a highly regulated process that is perturbed in human cancers, often through activation of the PI3K/mTOR pathway which impacts directly on the ribosome recruitment phase of translation initiation. While significant research has focused on "drugging" components of the PI3K/mTOR network, efforts have also been directed towards inhibiting eukaryotic initiation factor (eIF) 4F-dependent translation. Small molecule inhibitors of this complex have been identified, characterized, and used to validate the rationale of targeting this step to curtail tumor cell growth and modulate chemotherapy response. One such class of compounds are the rocaglates, secondary metabolites from the plant genus Aglaia, which target the RNA helicase subunit of eIF4F, eIF4A. Here we explore the ability of synthetic derivatives of aglaiastatins and an aglaroxin derivative to target the translation process in vitro and in vivo and find the synthetic derivative oxo-aglaiastatin to possess such activity. Oxo-aglaiastatin inhibited translation in vitro and in vivo and synergized with doxorubicin, ABT-199 (a Bcl-2 antagonist), and dexamethasone when tested on hematological cancer cells. The biological activity of oxo-aglaiastatin was shown to be a consequence of inhibiting eIF4A1 activity.