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Transnational and organized crime has become more prominent in the Pacific region in recent years, leading to challenges for law enforcement agencies in the region. The production and trafficking of illicit drugs are common concerns that illustrate the nexus between transnational and local crime landscapes. This article discusses approaches to the policing of such crime used by Pacific law enforcement agencies and regional partners. Informed by regional agreements, national security strategies of Pacific Islands governments, and theory about security networks, the article argues that plural and hybrid policing approaches, more commonly associated with community policing, may be effective models to combat drug-related crime. These approaches can involve cultural, social, and hierarchical webs that act as security nodes or networks on the frontline against illicit activities. Given different strengths and weaknesses of the various approaches available, an integrated and multifaceted approach to addressing drug-related crime offers the best chance of success.

Cities are becoming smarter and more optimized because of digital transformation, reducing costs, increasing safety, attracting investment, ensuring sustainability, and increasing viability. As a result of this optimization, they are becoming smart cities. Smart cities use the Internet of Things' devices, such as connected sensors, lights, and smart meters, to improve infrastructure and design by gathering and analyzing real-time citizen data. In this research, different conceptions of smart cities and their interconnections with digital transformation are presented. Therefore, the purpose of this chapter is to analyze how digital transformation may help manage smart cities. As a result, a thorough and integrated evaluation of the SCOPUS database will be conducted in order to address the following questions: (1) What are smart cities? (2) What is digital transformation? (3) How does digital transformation help to manage smart cities? The results point out that technologies and digital abundance, which include artificial intelligence, blockchain, and Internet of Things, play a crucial role in managing a controlled and automated infrastructure in smart cities. These favor the development of suitable places to live, work, and have fun, with a better quality of life for everyone.

concentrations of drugs

antibodies

Supplementary materials and methods

Novel covalent inhibitors of KRASG12C have shown limited response rates in patients with KRASG12C-mutant (MT) colorectal cancer. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed. Small-molecule KRASG12C inhibitors AZ’1569 and AZ’8037 were used. To identify novel candidate combination strategies for AZ’1569, we performed RNA sequencing, siRNA, and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT colorectal cancer cells and in vivo. AZ’1569-resistant colorectal cancer cells were generated and characterized. We found that response to AZ’1569 was heterogeneous across the KRASG12CMT models. AZ’1569 was ineffective at inducing apoptosis when used as a single agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the antiapoptotic BH3-family member BCL2L1/Bcl-xL as a top hit mediating resistance to AZ’1569. Further analyses identified acute increases in the proapoptotic protein BIM following AZ’1569 treatment. ABT-263 (navitoclax), a pharmacologic Bcl-2 family inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ’1569. Furthermore, this combination also resulted in dramatically attenuated tumor growth in KRASG12CMT xenografts. Finally, AZ’1569-resistant cells showed amplification of KRASG12C, EphA2/c-MET activation, increased proinflammatory chemokine profile and cross-resistance to several targeted agents. Importantly, KRAS amplification and AZ’1569 resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. Taken together, combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for patients with KRASG12CMT colorectal cancer.

Supplementary figures

BACKGROUND Highly detailed and invasive clinical investigations are needed to stratify haematuria patients with no disease, benign disease, and malignant disease. Due to the heterogeneity in the patient population and wide range of potential causes of haematuria, possibility to indicate patient-specific biomarkers could improve and speed up diagnostic process, which is crucial for patients with suspected cancer. OBJECTIVE We developed a new algorithm to identify risk of bladder cancer in haematuria patients by analyzing multiple urine and serum biomarkers and identifying the most significant using complex network theory. METHODS We analyzed data collected in the HABIO case – control study of haematuria patients, containing 675 participants (190 females, 485 males) aged between 40 and 80 years. In the study, we used the initial analysis pipeline of our Self-Supervised Semantic Learning (3SL) framework grounded on the complex network theory to stratify participants into two groups: healthy (with no clear cause of haematuria) or sick (with bladder cancer, infection etc.). We compared our model sensitivity and specificity with logistic regression and binary decision tree outcomes. To assess model performance, we used balanced accuracy to account for imbalance between the number of healthy and sick participants in the dataset. Additionally, to assess how linearly separable the biomarkers were, we applied k-means clustering. RESULTS Our modelling outperformed logistic regression and binary decision trees obtaining balance accuracies of 0.693 (females) and 0.715 (males) vs 0.621 (females) and 0.533 (males) for logistic regression and 0.570 (females) and 0.597 (males) for binary trees. K-means clustering showed that the distribution of the biomarkers did not match clear macro-patterns. For the sick population (both genders) the most significant biomarkers were previously associated with infectious diseases and inflammation (thrombomodulin, sTNFRII and osmolarity) or bladder cancer (IL-8, TGF-β). Additionally, CXCL16, midkine, clusterin, CEA, 8-OHdG were previously described in the literature as a potential biomarker for urinary tract cancers. CONCLUSIONS In the study we applied a new algorithm to improve diagnosis of haematuria in study participants. The algorithm performs better than currently widely applied methods (logistic regression, binary trees, k-means clustering). Additionally, applying 3SL algorithm we identified biomarkers most relevant for the specific group of patients and dependencies between those biomarkers. We hope that our results can guide further research and provide new personalised diagnostic tools directly tailored to individual patients' needs. CLINICALTRIAL Ethical approval was obtained from the Office of Research Ethics Committee Northern Ireland (11/NI/0164).

Novel covalent inhibitors of KRASG12C have shown limited response rates in patients with KRASG12C-mutant (MT) colorectal cancer. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed. Small-molecule KRASG12C inhibitors AZ’1569 and AZ’8037 were used. To identify novel candidate combination strategies for AZ’1569, we performed RNA sequencing, siRNA, and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT colorectal cancer cells and in vivo. AZ’1569-resistant colorectal cancer cells were generated and characterized. We found that response to AZ’1569 was heterogeneous across the KRASG12CMT models. AZ’1569 was ineffective at inducing apoptosis when used as a single agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the antiapoptotic BH3-family member BCL2L1/Bcl-xL as a top hit mediating resistance to AZ’1569. Further analyses identified acute increases in the proapoptotic protein BIM following AZ’1569 treatment. ABT-263 (navitoclax), a pharmacologic Bcl-2 family inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ’1569. Furthermore, this combination also resulted in dramatically attenuated tumor growth in KRASG12CMT xenografts. Finally, AZ’1569-resistant cells showed amplification of KRASG12C, EphA2/c-MET activation, increased proinflammatory chemokine profile and cross-resistance to several targeted agents. Importantly, KRAS amplification and AZ’1569 resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. Taken together, combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for patients with KRASG12CMT colorectal cancer.

PurposeNovel covalent inhibitors of KRASG12C have shown limited response rates in KRASG12C mutant (MT) colorectal cancer (CRC) patients. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed.Experimental designSmall molecule KRASG12C inhibitors AZ’1569 and AZ’8037 were employed. To identify novel candidate combination strategies for AZ’1569, we performed RNA sequencing, siRNA and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT CRC cells and in vivo. AZ’1569-resistant CRC cells were generated and characterised.ResultsResponse to AZ’1569 was heterogeneous across the KRASG12CMT models. AZ’1569 was ineffective at inducing apoptosis when used as single-agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the anti-apoptotic BH3-family member BCL2L1/Bcl-xL as a top hit mediating resistance to AZ’1569. Further analyses identified acute increases in the pro-apoptotic protein BIM following AZ’1569 treatment. ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ’1569. Furthermore, this combination also resulted in dramatically attenuated tumour growth in KRASG12CMT xenografts. Finally, AZ’1569-resistant cells showed amplification of KRASG12C, EphA2/c-MET activation, increased pro-inflammatory chemokine profile and cross-resistance to several targeted agents. Importantly, KRAS amplification and AZ’1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification.ConclusionsCombinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRASG12CMT CRC patients.

Purpose: The current study aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date, as well as aiming to determine the effect of AMD-associated genetic variants on metabolite levels and investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways. Design: Case-control association analysis of metabolomics data. Participants: Five European cohorts consisting of 2267 AMD patients and 4266 control participants. Methods: Metabolomics was performed using a high-throughput proton nuclear magnetic resonance metabolomics platform, which allows quantification of 146 metabolite measurements and 79 derivative values. Metabolome–AMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d-to-C3 ratio) were investigated using linear regression. Main Outcome Measures: Metabolites associated with AMD. Results: We identified 60 metabolites that were associated significantly with AMD, including increased levels of large and extra-large high-density lipoprotein (HDL) subclasses and decreased levels of very low-density lipoprotein (VLDL), amino acids, and citrate. Of 52 AMD-associated genetic variants, 7 variants were associated significantly with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, and LIPC) with metabolites belonging to the large and extra-large HDL subclasses. Also, 57 of 60 metabolites were associated significantly with complement activation levels, independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation. Conclusions: Lipoprotein levels were associated with AMD-associated genetic variants, whereas decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD.

EnglishIn the case of the Outermost Islands, which are heavily dependent on tourism and are inherently heavily dependent on air and sea connections to the issuing markets, a systematic analysis of the resources applied is imperative. Thus, this study developed a methodology for analyzing the financial viability of the expected return on this investment, meeting the promotion plans prepared and in accordance with the supply and demand conditions. This methodology is based on the bibliographic review of the different financial models of investment valuation and the indicators referred to in the tourism promotion plans. In the case of the Autonomous Region of Madeira, given the importance of tourism, the proposed methodology aims to be one instrument for supporting decision, according to the Index of Promotion Profitability. With the application of the model it is possible to determine for the promotion plan in the study, a promotion profitability index of €44.31, higher than the historical promotion profitability index of €42.50. portuguesNo caso de Ilhas Ultraperifericas, fortemente dependentes do turismo e por inerencia dependentes da ligacao aerea e maritima aos mercados emissores, e imperioso a analise sistematica dos recursos aplicados em promocao. Assim, desenvolveu-se uma metodologia de analise de viabilidade financeira do retorno expectavel desse investimento, atendendo aos planos de promocao elaborados e de acordo com as condicionantes de oferta e procura. Esta metodologia assenta na revisao bibliografica dos diferentes modelos financeiros de avaliacao de investimentos e nos indicadores referidos nos mesmos documentos. No caso particular da Regiao Autonoma da Madeira, dada a importância que o Turismo detem, a metodologia preconizada pretende ser um instrumento de apoio a decisao, em funcao do Indice de Rendibilidade em Promocao. Com a aplicacao da modelo e possivel determinar para o plano de promocao um indice de rendibilidade de promocao de 44,31€, superior ao indice de rendibilidade de promocao historico de 42,50€.

3557 Background: Novel covalent inhibitors of KRASG12C have shown modest response rates in KRASG12C mutant (MT) colorectal cancer (CRC) patients. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed. Methods: The small molecule KRASG12C inhibitors AZ’1569 and AZ’8037 were employed. To identify novel candidate combination strategies for AZ’1569, we performed RNA sequencing, siRNA and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT CRC cells and in vivo xenograft models. AZ’1569 acquired resistant CRC models were generated and characterised. Results: Response to AZ’1569 was heterogeneous across the KRASG12CMT models. AZ’1569 was ineffective at inducing apoptosis when used as a single agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the anti-apoptotic BH3-family member BCL2L1/Bcl-xL as top hit mediating resistance to AZ’1569. Further analyses identified acute increases in the pro-apoptotic protein BIM following AZ’1569 treatment. ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ’1569 in a panel of KRASG12C MT CRC cells. Furthermore, this combination also resulted in dramatically attenuated tumour growth in KRASG12C MT CRC xenografts. Finally, AZ’1569 acquired resistant KRASG12C MT CRC cells showed amplification of KRASG12C, EphA2/c-MET activation, increased pro-inflammatory chemokine profile and cross-resistance to standard-of-care chemotherapy and several targeted agents. Importantly, the KRAS amplification and AZ’1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. Conclusions: Combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12CMT CRC patients. The cross-resistance to other targeted therapies and importantly conventional chemotherapy in the AZ’1569 acquired resistant cells poses a challenge, with implications for the optimal use of KRASG12C inhibitors as a second or third line option.

Editorial EJKM Volume 18 Issue 3: Advances in Health Knowledge Management: New Perspectives by Maria Jose Sousa, Francesca Dal Mas and Renato Lopes Da Costa