bluuebunny/crossref_metadata_2025 huggingface dataset:
Partners at Care Transitions (PACT)—exploring older peoples’ experiences of transitioning from hospital to home in the UK: protocol for an observation and interview study of older people and their families to understand patient experience and involvement in care at transitions
Authors: Hardicre Natasha Kate , Birks Yvonne , Murray Jenni , Sheard Laura , Hughes Lesley , Heyhoe Jane , Cracknell Alison , Lawton Rebecca
Published: December 2017

Introduction

Length of hospital inpatient stays have reduced. This benefits patients, who prefer to be at home, and hospitals, which can treat more people when stays are shorter. Patients may, however, leave hospital sicker, with ongoing care needs. The transition period from hospital to home can be risky, particularly for older patients with complex health and social needs. Improving patient experience, especially through greater patient involvement, may improve outcomes for patients and is a key indicator of care quality and safety. In this research, we aim to: capture the experiences of older patients and their families during the transition from hospital to home, and identify opportunities for greater patient involvement in care, particularly where this contributes to greater individual-level and organisational-level resilience.

Methods and analysis

A ‘focused ethnography’ comprising observations, ‘Go-Along’ and semistructured interviews will be used to capture patient and carer experiences during different points in the care transition from admission to 90 days after discharge. We will recruit 30 patients and their carers from six hospital departments across two National Health Service (NHS) Trusts. Analysis of observations and interviews will use a framework approach to identify themes to understand the experience of transitions and generate ideas about how patients could be more actively involved in their care. This will include exploring what ‘good’ care at transitions looks like and seeking out examples of success, as well as recommendations for improvement.

Ethics and dissemination

Ethical approval was received from the NHS Research Ethics Committee in Wales. The research findings will add to a growing body of knowledge about patient experience of transitions, in particular providing insight into the experiences of patients and carers throughout the transitions process, in ‘real time’. Importantly, the data will be used to inform the development of a patient-centred intervention to improve the quality and safety of transitions.
Multiple and multidimensional transitions from trainee to trained doctor: a qualitative longitudinal study in the UK
Authors: Gordon Lisi , Jindal-Snape Divya , Morrison Jill , Muldoon Janine , Needham Gillian , Siebert Sabina , Rees Charlotte
Published: December 2017

Objectives

To explore trainee doctors’ experiences of the transition to trained doctor, we answer three questions: (1) What multiple and multidimensional transitions (MMTs) are experienced as participants move from trainee to trained doctor? (2) What facilitates and hinders doctors’ successful transition experiences? (3) What is the impact of MMTs on trained doctors?

Design

A qualitative longitudinal study underpinned by MMT theory.

Setting

Four training areas (health boards) in the UK.

Participants

20 doctors, 19 higher-stage trainees within 6 months of completing their postgraduate training and 1 staff grade, associate specialist or specialty doctor, were recruited to the 9-month longitudinal audio-diary (LAD) study. All completed an entrance interview, 18 completed LADs and 18 completed exit interviews.

Methods

Data were analysed cross-sectionally and longitudinally using thematic Framework Analysis.

Results

Participants experienced a multiplicity of expected and unexpected, positive and negative work-related transitions (eg, new roles) and home-related transitions (eg, moving home) during their trainee–trained doctor transition. Factors facilitating or inhibiting successful transitions were identified at various levels: individual (eg, living arrangements), interpersonal (eg, presence of supportive relationships), systemic (eg, mentoring opportunities) and macro (eg, the curriculum provided by Medical Royal Colleges). Various impacts of transitions were also identified at each of these four levels: individual (eg, stress), interpersonal (eg, trainees’ children spending more time in childcare), systemic (eg, spending less time with patients) and macro (eg, delayed start in trainees’ new roles).

Conclusions

Priority should be given to developing supportive relationships (both formal and informal) to help trainees transition into their trained doctor roles, as well as providing more opportunities for learning. Further longitudinal qualitative research is now needed with a longer study duration to explore transition journeys for several years into the trained doctor role.
Application of time series analysis in modelling and forecasting emergency department visits in a medical centre in Southern Taiwan
Authors: Juang Wang-Chuan , Huang Sin-Jhih , Huang Fong-Dee , Cheng Pei-Wen , Wann Shue-Ren
Published: December 2017

Objective

Emergency department (ED) overcrowding is acknowledged as an increasingly important issue worldwide. Hospital managers are increasingly paying attention to ED crowding in order to provide higher quality medical services to patients. One of the crucial elements for a good management strategy is demand forecasting. Our study sought to construct an adequate model and to forecast monthly ED visits.

Methods

We retrospectively gathered monthly ED visits from January 2009 to December 2016 to carry out a time series autoregressive integrated moving average (ARIMA) analysis. Initial development of the model was based on past ED visits from 2009 to 2016. A best-fit model was further employed to forecast the monthly data of ED visits for the next year (2016). Finally, we evaluated the predicted accuracy of the identified model with the mean absolute percentage error (MAPE). The software packages SAS/ETS V.9.4 and Office Excel 2016 were used for all statistical analyses.

Results

A series of statistical tests showed that six models, including ARIMA (0, 0, 1), ARIMA (1, 0, 0), ARIMA (1, 0, 1), ARIMA (2, 0, 1), ARIMA (3, 0, 1) and ARIMA (5, 0, 1), were candidate models. The model that gave the minimum Akaike information criterion and Schwartz Bayesian criterion and followed the assumptions of residual independence was selected as the adequate model. Finally, a suitable ARIMA (0, 0, 1) structure, yielding a MAPE of 8.91%, was identified and obtained as Visitt=7111.161+(at+0.37462 at−1).

Conclusion

The ARIMA (0, 0, 1) model can be considered adequate for predicting future ED visits, and its forecast results can be used to aid decision-making processes.
Validation of the grown-ups with congenital heart disease score
Authors: Hörer Jürgen , Roussin Régine , LeBret Emanuel , Ly Mohamed , Abdullah Jarrah , Marzullo Rafaella , Pabst von Ohain Jelena , Belli Emre
Published: December 2017

Objectives

Adults with congenital heart disease in need of heart surgery frequently present with significant comorbidity. Furthermore, additional technical difficulties often related to redo operations increase the risk for postoperative mortality and morbidity. Hence, next to the type of the procedure, additional procedure-dependent and procedure-independent factors have to be considered for risk evaluation. The recently proposed grown-ups with congenital heart disease (GUCH) mortality and morbidity scores account for these additional risk factors. We sought to validate their predictive power in a large population operated in a single centre.

Methods

Data of all consecutive patients aged 18 years or more, who underwent surgery for congenital heart disease between 2005 and 2016, were collected. Mortality was defined as hospital mortality or mortality within 30 days following surgery. Morbidity was defined as occurrence of one or more of the following complications: renal failure requiring dialysis, neurologic deficit persisting at discharge, atrioventricular block requiring permanent pacemaker implantation, mechanical circulatory support, phrenic nerve injury and unplanned reoperation. The discriminatory power of the GUCH scores was assessed using the area under the receiver operating characteristics curve (c-index, including 95% CI).

Results

Eight hundred and twenty-four operations were evaluated. Additional procedure-dependent and procedure-independent factors, as defined in the GUCH scores, were present in 165 patients (20.0%) and 544 patients (66.0%), respectively. Hospital mortality and morbidity was 3.4% and 10.0%, respectively. C-index for GUCH mortality score was 0.809 (0.742–0.877). C-index for GUCH morbidity score was 0.676 (0.619–0.734).

Conclusions

We could confirm the good predictive power of the GUCH mortality score for postoperative mortality in a large population of adults with congenital heart disease.
Cascading ecological effects from local extirpation of an ecosystem engineer in the Arava desert
Authors: Shanas Uri , Gavish Yoni , Bernheim Mai , Mittler Shacham , Olek Yael , Tal Alon
Published: December 2017

The extinction of a single species from a local community may carry little cost in terms of species diversity, yet its loss eliminates its biotic and abiotic interactions. We describe such a scenario in the Arava desert, where different cultural and law enforcement practices exclude Dorcas gazelles (Gazella dorcas (Linnaeus, 1758)) from the Jordanian side of the border while protecting their populations on the Israeli side. We found that gazelles break the soil crust, formed in desert systems after annual flooding, thereby creating patches of loose and cooler sand that are used by pit-building antlions (Neuroptera: Myrmeleontidae). When we artificially broke the soil crust on both sides of the border, we found a significant increase in antlion density in these patches, but only on the Israeli side. On the Jordanian side, where no gazelles have been observed since the early 1980s, no antlions colonized either control or manipulated plots. Additional choice/no-choice feeding experiments, in which we offered antlions to lizards and birds, revealed that the effect of humans on gazelles cascades farther, as antlions serve as a palatable food source for both groups. Thus, the human-mediated loss of nontrophic interactions between gazelles and antlions cascades to the loss of trophic interactions between antlions and their predators.
Vertical screening distances for total petroleum hydrocarbon for vapour intrusion risk assessment at petroleum underground storage tank sites
Authors: Lahvis Matthew A.
Published: December 2017

The US Environmental Protection Agency Office of Underground Storage Tanks (US EPA OUST) and Interstate Technology and Regulatory Council (ITRC) have recently published guidance indicating that buildings separated from light non-aqueous phase liquid (LNAPL) sources by more than 15 ft (4.6 m) are not a concern for vapour intrusion at petroleum underground storage tank (UST) sites. At this distance, there is a greater than 95% probability that soil gas concentrations for all key constituents of potential concern are below risk-based screening levels (RBSLs) between the LNAPL source and building foundation. Vertical screening distances for bulk Total Petroleum Hydrocarbon (TPH), common TPH fractions (C
5
–C
8
aliphatics, C
9
–C
12
aliphatics, and C
9
–C
10
aromatics), and indicator compounds (
n
-hexane and naphthalene) are less certain, however, because of a general lack of empirical data and highly variable soil-gas RBSLs. This study addresses these gaps through a statistical analysis of hundreds of soil-gas samples collected above LNAPL sources at more than 30 petroleum UST release sites. Resulting vertical screening distances for the various TPH fractions range between 0 and 7 ft (2.1 m) depending primarily on soil-gas RBSLs, which vary by over 5 orders of magnitude. Vertical screening distances for naphthalene are generally <3 ft (0.91 m). Vertical screening distances for
n
-hexane range from 12 (3.7) to 16 ft (4.9 m) and vary geographically. Vertical screening distances for total (bulk) TPH generally exceed 15 ft (4.6 m). Petroleum vapour intrusion risk assessments involving total (bulk) TPH are not recommended, however, because of uncertainties in quantifying soil-gas and indoor-air concentrations and defining RBSLs for fuel mixtures with variable source composition, toxicity, and fate and transport properties. Overall, the findings of this study validate the 15-ft screening distance recommended by ITRC and US EPA for application at petroleum UST sites with LNAPL sources.
RaTrace: simple and efficient abstractions for BVH ray traversal algorithms
Authors: Pérard-Gayot Arsène , Weier Martin , Membarth Richard , Slusallek Philipp , Leißa Roland , Hack Sebastian
Published: December 2017

In order to achieve the highest possible performance, the ray traversal and intersection routines at the core of every high-performance ray tracer are usually hand-coded, heavily optimized, and implemented separately for each hardware platform—even though they share most of their algorithmic core. The results are implementations that heavily mix algorithmic aspects with hardware and implementation details, making the code non-portable and difficult to change and maintain.

In this paper, we present a new approach that offers the ability to define in a functional language a set of conceptual, high-level language abstractions that are optimized away by a special compiler in order to maximize performance. Using this abstraction mechanism we separate a generic ray traversal and intersection algorithm from its low-level aspects that are specific to the target hardware. We demonstrate that our code is not only significantly more flexible, simpler to write, and more concise but also that the compiled results perform as well as state-of-the-art implementations on any of the tested CPU and GPU platforms.
Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer
Authors: Chen Chun-Chin , Feng Weiran , Lim Pei Xin , Kass Elizabeth M. , Jasin Maria
Published: December 2017

Germ-line and somatic mutations in genes that promote homology-directed repair (HDR), especially BRCA1 and BRCA2, are frequently observed in several cancers, in particular, breast and ovary but also prostate and other cancers. HDR is critical for the error-free repair of DNA double-strand breaks and other lesions, and HDR factors also protect stalled replication forks. As a result, loss of BRCA1 or BRCA2 poses significant risks to genome integrity, leading not only to cancer predisposition but also to sensitivity to DNA-damaging agents, affecting therapeutic approaches. Here we review recent advances in our understanding of BRCA1 and BRCA2, including how they genetically interact with other repair factors, how they protect stalled replication forks, how they affect the response to aldehydes, and how loss of their functions links to mutation signatures. Importantly, given the recent advances with poly(ADP-ribose) polymerase inhibitors (PARPi) for the treatment of HDR-deficient tumors, we discuss mechanisms by which BRCA-deficient tumors acquire resistance to PARPi and other agents.
Effect of Pretreatment with Sulfuric Acid on Catalytic Hydrocracking of Fe/AC Catalysts
Authors: Wang Ruiyu , Wang Fei , Liu Ling
Published: December 2017

Activated carbon (AC) was modified by H2SO4 and used as a support for catalyst. The Fe2S3/AC-T catalyst was prepared by deposition-precipitation method and used to catalyze hydrocracking of coal-related model compound, di(1-naphthyl)methane (DNM). The properties of catalyst were studied by N2 adsorption-desorption, X-ray diffraction, and scanning electron microscopy. The result showed that ferric sulfate and acidic centers had synergetic effect on hydrocracking of DNM when using Fe2S3/AC-T as catalyst, the optimal loading of Fe is 9 wt.%. Hydroconversion of the extraction residue from Guizhou bituminous coal was also studied using Fe2S3/AC-T as the catalyst. The reaction was conducted in cyclohexane under 0.8 Mpa of initial hydrogen pressure at 310°C. The reaction mixture was extracted with petroleum ether and analyzed by GC/MS. Amounts of organic compounds which fall into the categories of homologues of benzene and naphthalene were detected. It suggested that the catalyst could effectively catalyze the cleavage of C-C-bridged bonds.
Abstract A15: The relationship between cervical cancer associated genes and human papilloma viruses in rural Africans in Zaria
Authors: Idoko John , Faruk Mohammed , Yaro Jigo Dangude , Enemari James Oluwa , Akpulu Peter
Published: December 2017

Cervical cancer is a major public health problem and one of the leading gynecological cancers in developing nations. Reports from Nigeria, the largest black nation in the world by population, show that the national incidence of cervical cancer is 250/100,000. We sought to evaluate the relationship between cervical cancer associated genes and human papilloma viruses from rural Africans in Zaria, Nigeria using immunohistochemistry and molecular phylogenetics. Selected cervical cancer associated genes sequences which include Ki-67 (NM_002417.4), p53 (AB082923.1), EGFR (NM_005228.3), MYC (M25803.1), KRAS (EF471957.1), TGF-B (AF254794.1) and RB (AH002963.2) genes and HPV 16 (KJ869425.1 E6 and E7 variants), HPV 18 (KJ869426.1), HPV 45 (S40261.1), HPV 6 (A25369.1), HPV 11 (J04351.1), HPV 31 (KJ869427.1) and HPV 33 (KJ869428.1) sequences were retrieved from the gene bank data base. The sequences were aligned and bootstrap at 2000 bp to create a molecular phylogenetic tree. Haematoxylin and Eosin together with immunohistochemistry were performed on fifty formalin-fixed paraffin-embedded (FFPE) tissue blocks using Anti- Ki-67, p53, EGFR, MYC, KRAS, TGF-B and RB monoclonal antibodies. Result from the phylogenetic analysis reveals trichotomized tree showing apparent significant evolutionary relationship between cladogram of HPV16 and MYC; HPV18, HPV6 and KRAS genes; EGFR gene and HPV45. Immunohistochemistry results show multivariate expression of Ki-67, p53, EGFR, MYC, KRAS, TGF-B and RB of proteins from the cervical cancer tissue blocks used. Combination of Ki-67 biomarker and other cervical cancer associated genes together with HPV subtypes-genotyping can serve as useful instruments in proper management of the disease.

Citation Format: John Idoko, Mohammed Faruk, Jigo Dangude Yaro, James Oluwa Enemari, Peter Akpulu. The relationship between cervical cancer associated genes and human papilloma viruses in rural Africans in Zaria [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A15.
Abstract A33: Population and evolutionary genomics of prostate cancer-associated variants: implications for health disparities in men of African descent
Authors: Lachance Joseph , Berens Ali , Hansen Matthew , Teng Andrew , Tishkoff Sarah , Rebbeck Timothy
Published: December 2017

To determine why African men are more likely to suffer from prostate cancer (CaP), we integrated GWAS results and scans of selection with allele frequency data from 64 global populations. Despite substantial overlap in genetic risk scores across populations, we find that predicted CaP risk is highest in West Africans and that a small number of loci drive these differences in risk. There is a strong concordance between genetic risk scores and clinical estimates of CaP mortality. Although most CaP-associated loci are evolving neutrally, we find multiple instances where alleles have hitchhiked to high frequencies with linked locally adaptive alleles.

Citation Format: Joseph Lachance, Ali Berens, Matthew Hansen, Andrew Teng, Sarah Tishkoff, Timothy Rebbeck. Population and evolutionary genomics of prostate cancer-associated variants: implications for health disparities in men of African descent [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A33.
Abstract B18: MAGEC1 and BAGE2 mRNA expression can be used to monitor chemotherapy treatment responses in multiple myeloma patients and pre-empt clinical relapse
Authors: Shires Karen , Wienand Kirsty
Published: December 2017

Being able to monitor the levels of malignant progenitor cells in Multiple Myeloma, as opposed to the plasma cell burden or clinical symptoms alone, will be an important move forward in the management of this disease. The expression of cancer testis antigen MAGE C1 has been previously linked to the malignant stem cell at all stages of this disease, while BAGE2 expression has been clearly associated with the progression to a more advanced disease stage and thus clonal evolution. We investigated the use of a multiplex QRTPCR approach to monitor the co-expression of these transcripts in the peripheral blood as an alternative monitoring methodology. We compared the levels of MAGEC1 and BAGE2 mRNA in the PBMC population to serum M protein and serum beta 2 microglobulin levels at 3-monthly intervals over a 2-year period for 12 patients on chemotherapy regimens. The analysis indicated that the novel QRTPCR analysis of MAGE C1 expression in the less invasive peripheral blood sample type was extremely relevant as a potential minimal residual disease-monitoring tool. Expression of this cancer testis antigen was detectable in all patients throughout treatment, with comparable increases and decreases to serum M protein and/or serum beta 2 microglobulin, but with the advantage of being able to detect disease at a lower level and potentially signal relapse prior to a full clinical relapse. Expression of BAGE2 was only observed in a few patients, but its expression was clearly associated with a worsening clinical profile. As with MAGEC1, the detection of this transcript occurred at least 3 months prior to clinical changes in some patients, indicating its potential use in early medical intervention.

Citation Format: Karen Shires, Kirsty Wienand. MAGEC1 and BAGE2 mRNA expression can be used to monitor chemotherapy treatment responses in multiple myeloma patients and pre-empt clinical relapse [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B18.
Abstract B27: Unusual presentations of prostate cancer
Authors: Mante Sunny Doodu , Adusei Benjamin , Snyper Nana Yaa
Published: December 2017

Unusual presentations of prostate cancer can usually mislead the Surgeon in the management of his patient. Prostate cancer may presents in such a way that it mimics other conditions such as generalized lymphadenopathy, Supraclavicular lymphadenopathy, dyspnoea, chronic constipation, and ureteric obstruction. Most of these cases have no lower urinary tract symptoms and the main clue is to do a digital rectal examination which is abnormal, an elevated PSA and a TRUS biopsy to make the diagnosis. Treatment is usually with Bicalutamide and LHRH analogues. This leads to resolution of the condition.

Citation Format: Sunny Doodu Mante, Benjamin Adusei, Nana Yaa Snyper. Unusual presentations of prostate cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B27.
Abstract B31: The role of HIV protein Nef in the development of HIV/AIDS-associated lymphomas
Authors: Mowla Shaheen , Mdletshe Nontlantla
Published: December 2017

Introduction: The pathogenesis HIV-associated lymphomas involve a complex interplay of biological factors, including the immerging role of HIV encoded proteins. These proteins have been shown to have oncogenic potential and to enhance the pathogenesis of HIV-associated malignancies. However, very little is known about the molecular mechanisms involved in this interaction. Here, we investigate the effect of HIV protein Negative Factor (Nef) on the expression of c-MYC and activation-induced cytidine deaminase (AID) in lymphoblasts and lymphoma cells.

Methods: Native histidine-tagged HIV Nef was produced in a bacterial system and used to treat (1) an EBV-immortalized B lymphoblastoid cell line (L1439A) and (2) the established lymphoma cell line Ramos, at various concentrations and for various time points. Changes in the expressions of c-MYC and AID were measured at both the mRNA and proteins levels using qPCR and western blotting respectively. The ability of Nef to regulate the promoter of these two genes was determined using luciferase reporter assays. Furthermore, confocal microscopy was used to investigate the downstream effects of Nef exposure.

Results: In L1439A cells, a general decrease in the expression of c-MYC and AID was observed. After 1 and 3 hours of exposure to HIV-Nef both c-MYC and AID mRNA levels reduced by approximately 0.5-fold. In contrast, the expressions of both genes increased significantly upon these treatments in the lymphoma cell line Ramos. After 3 hours of exposure, c-MYC expression increased by ~1.9-fold, while AID expression increased up to 4.6-fold. The protein expression followed a similar pattern, as indicated by western blotting. Furthermore, luciferase reporter assays showed that the effect on c-MYC expression is likely to be direct since the activity of the c-MYC promoter increased in a dose-dependent manner in the presence of Nef. c-MYC translocated to the nucleus, which is indicative of an active protein. Furthermore, an increase in gamma H2AX foci on DNA, indicative of double strand breaks, shows that the increase in AID lead to genomic instability.

Conclusion: This study demonstrates a differential effect of HIV Nef on normal immortalized lymphoblasts versus lymphoma cells. More importantly, it shows for the first time that HIV Nef may enhance the pathogenesis of lymphomas by triggering pathways and mechanisms which increase the expression of c-MYC and AID.

Citation Format: Shaheen Mowla, Nontlantla Mdletshe. The role of HIV protein Nef in the development of HIV/AIDS-associated lymphomas [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B31.
Abstract IA22: Emerging signaling pathways in prostate cancer therapy
Authors: Zerbini Luiz F.
Published: December 2017

One major prerequisite to develop targeted therapies is the identification of relevant cellular targets and the identification of the relevant patient population in which to test these therapies. Although androgen ablation therapy, surgery and radiation therapy are effective for the treatment of local prostate cancer (PCa), there is no effective treatment available for patients with metastatic disease. The receptor tyrosine kinase Axl has been implicated in the pathology of many cancers. Increased Axl expression correlates with metastasis, aggressive behavior, and poor survival and have been linked with resistance to chemotherapeutic regimens in tumors. Interestingly, in these reports inhibition of Axl leads to restoration of sensitivity to drug therapy, indicating that Axl may represent a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to some drugs.

We have shown that Axl is overexpressed in PCa and is an essential regulator of PCa proliferation and tumor growth. Axl expression is elevated in hormone-refractory PCa cell lines and Axl knockdown reduces migration and invasion and tumor formation in vivo. The Axl ligand, GAS6, acts as a growth and/or survival factor and its binding to Axl activates PI3K and its downstream targets S6K and Akt. Activation of these pathways has been reported to induce nuclear translocation of the transcription factor nuclear factor kappa B (NF-κB), IL-6 production and STAT3 activation.

The molecule named R428 (now renamed BGB324) inhibits in a dose-dependent manner Gas6 stimulated Axl autophosphorylation and activity with high specificity, selectivity, and affinity and blocks Axl-dependent signaling events, such as Akt phosphorylation, cell invasion, and pro-inflammatory cytokine production. R428/BGB324 effectively prevents or reverses acquired resistance to several cancer therapies in preclinical models. Most importantly, as a result of these and other encouraging preclinical findings of therapeutic value this first-in-class, highly selective Axl inhibitor has entered the clinical trial phase.

Docetaxel, the main chemotherapeutic drug used in aggressive prostate cancer treatment, has shown limited efficacy against metastatic PCa, primarily due to invariable development of drug resistance, necessitating a thorough investigation of the mechanisms underlying this drug resistance and the development of novel, more efficacious therapies to prevent or overcome resistance. Preliminary data from our laboratory provide strong evidence for the notion that Axl plays a pivotal role in resistance to docetaxel and possibly cabazitaxel treatment. Importantly, Axl inhibitor R428 enhances docetaxel efficacy.

Citation Format: Luiz F. Zerbini. Emerging signaling pathways in prostate cancer therapy [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA22.
Abstract IA3: The impact of premature death of women from preventable cancers, such as cervical cancer
Authors: Denny Lynette
Published: December 2017

Cervical cancer is the second most common cancer among women living in sub-Saharan Africa, yet more women die from cervical cancer than women with breast cancer. Despite cervical cancer being preventable, services for prevention, early detection and treatment are rare in most poorer countries, and most women die in the 4th-5th decade, a time when their children are particularly vulnerable, especially the girl child. The global adult mortality rate per 1000 population by WHO region in 2011 was 160, with the highest rate being in Lesotho at 541/1000. The under 5 mortality rate per 1000 live births in the African WHO region was 95/1000 in 2012 and 12 in Europe. The Gender Inequality Index (GII) is a composite index that reflects women's relative social disadvantage in three dimensions - reproductive health, empowerment and the labour market. Using the GII, among a number of other indices, it was found that overall women in developing countries had two-fold higher cervical cancer incidence rates and three-fold higher mortality rates than their counterparts from developed countries. Deprivation levels or poverty rates were a strong predictor of cross-national variations in cervical cancer incidence and mortality. Losing a parent, especially a mother for young girls may be catastrophic as her health and care is likely to deteriorate significantly. This paper will explore the range of effects of premature deaths of mothers on children in poor countries.

Citation Format: Lynette Denny. The impact of premature death of women from preventable cancers, such as cervical cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA3.
Abstract IA31: Precision prevention: Leveraging genomics to improve cancer control
Authors: Rebbeck Timothy R.
Published: December 2017

Most tumors are incurable once they reach an advanced (e.g., metastatic) stage. Even for those cancers with effective treatment options, prevention has the greatest potential to reduce the burden of cancer in the general population. Prevention has great potential to reduce the burden of cancer before it can cause illness and death. However, not all individuals respond to prevention strategies in the same way: an individual's unique genetic makeup and unique set of biological events that lead to cancer mean that each individual may require a personalized approach to prevention. Precision prevention can be defined as the use of biological, behavioral, socioeconomic, and epidemiological data to devise and implement strategies tailored to reducing cancer incidence and mortality in a specific individual or group of individuals.

In order to develop a precision prevention approach, it is critical that we understand: 1) basic biology of early carcinogenesis (e.g., genomic susceptibility, drivers of cancer, timing of carcinogenic events, reversibility of biological events); 2) heterogeneity (e.g., Inter-individual differences in susceptibility and tumor phenotype, intra-tumor differences in terms of clonality and propensity to metastasize, and response to preventive interventions); 3) unintended Effects of preventive strategies; and 4) implementation and health economics of preventive interventions.

The principles of precision prevention strategies include a focus on those individuals who are at highest risk of suffering or death from cancer (e.g., genetically high-risk individuals and individuals with pre-neoplasia), focus on interventions that are motivated by fundamental biological knowledge, have a favorable cost-benefit ratio, and benefit all populations, including underserved and minority groups.

In order for precision prevention to be successful, research is required to generate fundamental knowledge about cancer etiology and mechanism through scientific discovery; develop novel prevention strategies based on these fundamental discoveries; improve existing prevention strategies by incorporating biological information, biomarkers, risk profiling, and molecular subtyping to optimize prevention efficacy; and understand and implement cost-effective prevention strategies in targeted populations who are most likely to benefit.

Citation Format: Timothy R. Rebbeck. Precision prevention: Leveraging genomics to improve cancer control [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA31.
Abstract A10: CRISPR-AnalyzeR (caR): Web-based, interactive and exploratory analysis and documentation of pooled CRISPR/Cas9 screens
Authors: Winter Jan , Schwering Marc , Rauscher Benedikt , Heigwer Florian , Boutros Michael
Published: December 2017

Since the availability of the CRISPR/Cas9 gene editing technique, pooled CRISPR/Cas9 screens have become a powerful and versatile tool for the investigation of functional genomics in a variety of organisms. Pooled CRISPR/Cas9 screens are cost-effective and do not require lab automation, which allows even small labs to perform genome-wide genetic perturbation screens. The analysis of such screens so far requires in-depth knowledge in either bioinformatics or data analysis as there is a limited availability of end-to-end data analysis pipelines (Li et al., 2014; Winter et al., 2015). Moreover, the explorative analysis of screening data using end-to-end analysis tools often comes with certain limitations. Either these pipelines require sufficient computing power on the user machine or have to be run in command-line mode on dedicated machines, which constrains the usability.

A special need for wet-lab scientists is the availability of analysis pipelines which allow them to analyze the screening data on their own, knowing best about potential candidates and the biological background. Here we describe the CRISPR-AnalyzeR (caR), which is a web-based and fully-interactive tool to analyze pooled CRISPR/Cas9 screens meant for wet-lab scientists. caR combines both, end-to-end data analysis and explorative screen analysis that can be accessed via a regular web-browser such as Google Chrome or Firefox from any device - allowing the user to analyze the data in a comfortable, convenient and exploratory way. Moreover, caR uses latest visualization technologies to provide interactive plots and tables, allowing even novice users to analyze their own screens in an exploratory way. caR performs hit-calling using six different analysis methods, which gives the user the power and flexibility to select appropriate follow-up candidates. caR provides an easy-to-follow workflow and guides the user through the whole analysis process, which includes quality control, hit calling, in-depth gene information, data annotation enrichment and downloadable interactive reports to provide a comprehensive documentation.

Since caR is a web-based tool, it can be used via a provided web-server at http://crispr-analyzer.dkfz.de or can be downloaded for a local network installation.

Citation Format: Jan Winter, Marc Schwering, Benedikt Rauscher, Florian Heigwer, Michael Boutros. CRISPR-AnalyzeR (caR): Web-based, interactive and exploratory analysis and documentation of pooled CRISPR/Cas9 screens [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A10.
Abstract A15: Downregulation of c-myc is synthetic lethal with PARP inhibitors in high MYC cancers independent of BRCA status
Authors: Carey Jason PW , Vjayaraghavan Smruthi , Hunt Kelly , Keyomarsi Khandan
Published: December 2017

PARP inhibitors represent a novel class of cancer therapeutics that exploit a synthetic lethal mechanism specific to cancer cells with a defect within the Homologous Recombination (HR) DNA repair pathway. Patients with a BRCA1/2 germ-line mutation have the highest response rate to PARP inhibitors. However, early clinical trial data has indicated that only ~30-40% BRCA mutant patients respond to PARP inhibitors. Coincidentally, the oncogene c-myc is the most frequently amplified gene in BRCA mutant tumors (~40-60%) which typically present as Triple Negative Breast Cancer (TNBC). The oncogene c-myc transcriptionally regulates several DNA repair genes, and correlates with poor survival among breast cancer patients. Therefore we hypothesized that dual combination therapy targeting c-myc and PARP is an effective therapeutic strategy in BRCA mutant tumors. C-myc siRNA induced increased sensitivity to PARP inhibitors in BRCA wild-type (MB231) & BRCA mutant (SUM149) TNBC cell lines and down regulated HR repair. Pan CDK inhibitor Dinaciclib demonstrated significant MYC inhibition across several TNBC cell lines. Additionally, Dinaciclib demonstrated synergistic growth inhibition in combination with PARP inhibitor Niraparib in both BRCA wild-type and mutant c-myc expressing TNBC cell lines. Combination therapy also leads to an increase in DNA damage (via γH2AX) with a decrease in HR repair (BRCA1/RAD51). TNBC cell line mouse xenografts demonstrated down regulation of c-myc and RAD51 in Dinaciclib + Niraparib treated tumors. Dual Dinaciclib + Niraparib therapy also induced synergistic growth inhibition in PARP inhibitor acquired resistant cell lines while demonstrating significant growth inhibition across a panel of c-myc overexpressing cancer cell lines (Ovarian, Prostate, Pancreatic, Colon & Lung). In conclusion, we demonstrated that dual CDK + PARP inhibition is synthetic lethal in both BRCA wild-type and mutant TNBC cell lines and is dependent upon down regulation of c-myc. This study supports c-myc as predictor of response to PARP inhibitor therapy and may also serve as a biomarker of response to Dinaciclib + PARPi therapy in high MYC expressing tumors.

Citation Format: Jason PW Carey, Smruthi Vjayaraghavan, Kelly Hunt, Khandan Keyomarsi. Downregulation of c-myc is synthetic lethal with PARP inhibitors in high MYC cancers independent of BRCA status [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A15.
Abstract A18: Predicting synergistic drug combinations from genomic features and single-agent response profiles
Authors: Rees Matthew G. , Brenan Lisa , Walker Amanda , Johannessen Cory M.
Published: December 2017

Drug combinations promise to improve clinical responses and/or forestall drug resistance. To capitalize on this promise, we need to know which drugs to combine, and whom to give them to based on the genetic or pathological features of their disease. However, accomplishing this goal has been precluded by the infeasibility of performing comprehensive drug-combination studies across thousands of cellular contexts. We hypothesized that the basal gene-transcription state of cancer cell lines, in concert with the response profiles of hundreds of single-agent small molecules, might be leveraged to nominate synergistic drug combinations, eliminating the need to test all possible drug/drug combinations across cellular models. Specifically, we predicted that inhibiting the protein product of transcripts associated with drug resistance to a given small molecule might induce drug synergy. To test this notion, we analyzed public cell-line drug-sensitivity data to identify candidate compound-gene pairs. We identified 7 examples in which outlier expression of a druggable candidate protein was associated with lack of single-agent response. Inhibition of 6/7 candidate co-targets resulted in cell-line-specific synergistic cell killing across multiple cell line models, validating the overall approach. For example, consistent with clinical findings, we found that high expression of the MGMT gene, encoding O-6-methylguanine-DNA methyltransferase, was uniquely associated with response to alkylating agents such as temozolomide, and that combination of the MGMT inhibitor O-6-benzylguanine with temozolomide resulted in synergistic killing. These initial studies highlight the potential of integrating basal gene expression features with small-molecule response to nominate rational candidates for drug combinations. As public repositories of single-agent response data from diverse cellular contexts continue to expand, so too will our repertoire of therapeutic combinations. Moreover, this approach permits the parallel identification of genomic features that indicate which patient populations are most likely to benefit from such combinations.

Citation Format: Matthew G. Rees, Lisa Brenan, Amanda Walker, Cory M. Johannessen. Predicting synergistic drug combinations from genomic features and single-agent response profiles [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A18.
Abstract A19: Exploring genetic interactions in haploid human cells
Authors: Blomen Vincent A. , Brummelkamp Thijn R.
Published: December 2017

Gene-associated phenotypes often depend on the activity of other genes resulting in genetic interactions. In model organisms, the large-scale generation of combinations of mutations has resulted in the identification of genetic interactions and provided insights into their contribution to complex phenotypes. Here we use haploid human cells combined with genome-wide mutagenesis to study genetic interactions. We have made a synthetic lethality network using query genes acting in the secretory pathway and observe that human genes frequently engage in genetic interactions. Beyond cell lethality, we search for genes, which upon loss deregulate cellular processes such as signaling pathways. Genetic modifier approaches in those mutants reveals back-up mechanisms or genetic networks contributing to the phenotype of interest. This provides a much-needed window into the robust genetic networks governing human cells.

Citation Format: Vincent A. Blomen, Thijn R. Brummelkamp. Exploring genetic interactions in haploid human cells [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A19.
Abstract A38: Genome-wide CRISPR-Cas9 screens reveal modulators of temozolomide sensitivity in glioblastoma
Authors: MacLeod Graham , Rajakulendran Nishani , Hart Traver , Yu Helen , Dirks Peter B. , Angers Stephane
Published: December 2017

Glioblastoma (GBM) is a prevalent and highly lethal form of primary brain tumour. Presently, median survival time for GBM patients is only 15 months and thus improved treatment methods are in great need. Treatment of GBM consists of surgery, radiotherapy and the chemotherapeutic agent temozolomide (TMZ). Unfortunately, many GBMs are refractory to TMZ and most others ultimately develop resistance leading to localized disease recurrence and brain tumor invasion. With the aim of identifying new therapeutic targets for GBM we performed genome-wide CRISPR-Cas9 screens to identify genes that modulate TMZ sensitivity in GBM. The TKO library of single-guide RNAs (gRNAs) targeting over 89,000 exons in 17,232 human genes was used to screen a panel of 5 patient-derived human GBM stem cell (GSC) lines. GSCs treated with DMSO were grown in parallel with GSCs treated with either a lethal, or sub-lethal dose of TMZ. Next-generation sequencing was used to identify gRNAs that were increased/decreased in abundance in TMZ treated pools of cells.

Positive selection screening revealed that loss of key components of the mismatch repair pathway–MLH1, MSH2, MSH6 and PMS2 confers resistance to lethal doses of TMZ, as has previously been observed in GBM patients. Negative selection screening using sub-lethal doses of TMZ showed that loss of a conserved set of 15 genes that conferred TMZ hypersensitivity in four MGMT-negative GSC lines while the lone MGMT-positive GSC line in our set had a completely different set of hypersensitivity genes. Functional annotation revealed enrichment for genes involved in multiple DNA repair pathways, most prominently Fanconi Anemia and interstrand cross-link repair. Further studies validated that deletion of either member of the MCM8/9 helicase complex sensitizes GBM cells to TMZ and characterized the previously undescribed gene ZC3H7A which was revealed to be a cytoplasmic, stress-granule associated protein. In addition, our results revealed that in drug resistant MGMT expressing GSCs, TMZ resistance can be restored via the PARP inhibitor ABT-888.

In conclusion, our results have identified a core set of genes that can be targeted to increase sensitivity to the chemotherapeutic agent TMZ responsive GBMs and elucidated opportunities for restoring TMZ sensitivity in resistant GBMs. These genes, many of which are targetable enzymes represent promising therapeutic targets for increasing efficacy of chemotherapy and decreasing lethality in GBM.

Citation Format: Graham MacLeod, Nishani Rajakulendran, Traver Hart, Helen Yu, Peter B. Dirks, Stephane Angers. Genome-wide CRISPR-Cas9 screens reveal modulators of temozolomide sensitivity in glioblastoma [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A38.