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The potential of natural killer cells in pancreatic cancer : from exploring tumorinfiltrating lymphocytes to novel CAR-NK cell therapy
No full textABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is associated with high mortality rates due
to challenges in diagnosis and limited effective treatments. Natural killer (NK) cells
have emerged as a promising adoptive cell therapy for PDAC. These cells possess high
cytotoxic function, can recognize tumors independently of major histocompatibility
complex class I (MHC-I), and carry a low risk of toxicities, thus holding the potential to
improve cancer treatment.
Despite their promise, NK cell-based therapy faces challenges, such as limited in vivo
persistence, reduced tumor infiltration, and low cell numbers. Additionally, the
suppressive tumor microenvironment (TME) of solid tumors, particularly of pancreatic
cancer, leads to the dysfunction of both T and NK cells. To address this, strategies
exploring tumor-infiltrating lymphocytes (TILs) and developing novel chimeric
antigen receptor (CAR)-cells are being investigated.
This study characterized TIL-NK cells from central and peripheral tumor regions and
peripheral blood mononuclear cells (PBMCs) of patients diagnosed with PDAC. A
distinct distribution of NK cell infiltration within the TME was observed, with higher
numbers infiltrating peripheral regions. However, NK cells from central tumor regions
showed higher expansion rates than those infiltrating peripheral regions and PBMC.
Moreover, NK cells stimulated with IL-2, IL-15, and short IL-12 showed superior
expansion, activation, and cytotoxicity, indicating that the persistence and cytotoxicity
of TIL-NK cells can be improved ex vivo.
Genetic manipulation is another strategy to enhance NK cell function, including CARNK
cells with superior persistence, cytotoxicity, and tumor-targeting capacities.
Additionally, cytokine-induced memory-like (CIML) NK cells displayed increased
cytotoxicity and prolonged persistence. In this study, we engineered the 'Buddy-CAR'
system, consisting of CAR-CIML NK cells expressing IL7Rα and secreting IL-7
molecules. These engineered NK cells induced self-proliferation and activation,
independent of exogenous IL-2 or IL-15, and promoted the proliferation of surrounding
T cells.
Overall, these findings represent significant advancements in NK cell-based therapies
for solid tumors, particularly in the context of pancreatic cancer.RESUMO
O adenocarcinoma ductal do pâncreas (PDAC) está associado a elevadas taxas de
mortalidade, devido ao diagnóstico tardio e à eficácia limitada das opções
terapêuticas disponíveis. As células naturais citotóxicas (NK) emergem como uma
terapia celular promissora adotiva para o tratamento do PDAC. Estas células têm uma
função altamente citotóxica; conseguem reconhecer tumores independentemente
do complexo principal de histocompatibilidade classe I (MHC-I) e apresentam um
risco baixo de efeitos secundários, em comparação com outras imunoterapias,
podendo melhorar a eficácia do tratamento deste tipo de cancro.
Apesar das suas vantagens, a terapia baseada nas células NK enfrenta alguns desafios,
como a reduzida persistência in vivo, a infiltração tumoral limitada e um número total
de células reduzido. Adicionalmente, o microambiente tumoral (tumor
microenvironment, TME) dos tumores sólidos é altamente imunossupressor,
principalmente no contexto do cancro pancreático, o que promove a disfunção das
células T e NK. Para superar essas limitações, estão a ser investigadas várias
estratégias, incluindo o uso de linfócitos infiltrantes de tumores (tumor infiltrating
lymphocytes, TIL) e desenvolvendo de células geneticamente modificadas com
recetores antigénicos quiméricos (chimeric antigen receptor, CAR).
Um dos objetivos deste trabalho foi isolar e caracterizar células TIL-NK das regiões
central e periférica dos tumores de doentes com cancro do pâncreas, assim como das
células mononucleares do sangue periférico (peripheral blood mononuclear cells,
PBMC). Observou-se uma distribuição distinta na infiltração das células NK dentro do
TME, com um maior número de células infiltradas nas regiões da periferia.
Adicionalmente, as células NK das regiões centrais dos tumores apresentaram taxas
superiores de expansão em comparação com as células NK que infiltram as regiões
periféricas e presentes nas PBMCs. Além disso, neste estudo, as células NK
estimuladas com interleucinas (IL)-2, IL-15 e IL-12 demonstraram superior expansão,
ativação e citotoxicidade, indicando que as capacidades anti-tumorais destas células
podem ser melhoradas ex vivo.
Outra estratégia para melhorar a atividade anti-tumoral destas células é através da
sua manipulação genética, incluindo o desenvolvimento de células CAR-NK com
superior persistência, citotoxicidade e reconhecimento tumoral. Adicionalmente, as
células NK podem ainda adquirir capacidades de memória, com superior
citotoxicidade e perisistência, após estimulação com citoquinas, designando-se por
células (cytokine-induced memory-like) CIML NK. Neste estudo foi desenvolvido o
sistema ‘Buddy-CAR’, que consiste em células CAR-CIML NK que expressam IL7Rα e secretam moléculas de IL-7. Estas células não só promovem a sua própria ativação e
proliferação, independentemente da presença de IL-2 ou IL-15, como também
promovem a proliferação de células T circundantes.
Em conclusão, estes resultados representam avanços significativos nas terapias com
células NK para tumores sólidos, especialmente no contexto do cancro pancreático
How can saltpay successfully scale loyverse- business by entering new European markets? An analysis of the Danish e-pos market
No full textThe present work project answers how SaltPay, a payment service and software provider, aims
to gain market share and revenue growth in the e-POS industry. With SaltPay’s recent
acquisition Loyverse, the three most attractive European countries, namely Germany, Denmark,
and Italy, are identified in a country selection process. An in-depth analysis then evaluates the
attractivity of the Danish e-POS market. By employing qualitative and quantitative research,
this work project’s goal is to build an expansion and market entry strategy
Consulting lab: optimizing indie campers´ booking experience strategy from a revenue management perspective
No full textThe recreational vehicle (RV) rental market is growing steadily. Indie Campers, founded in
Portugal in 2013, provides RV rental and sales services. From a revenue management
perspective, the goal of this project was to enhance Indie Campers’ online booking experience
and ancillary product strategies for the rental business unit. This optimization aimed to elevate
Indie Campers’ e-commerce capabilities, fostering increased revenues. Embracing Indie
Campers’ preference for an empirical testing approach, the team developed practical strategic
recommendations to refine the booking experience and the communication, pricing, and
product strategies for ancillary products, the latter including distance packages, extras, and
protection plans
Consulting lab: optimizing indie campers´ extras and bundles strategy from a revenue management perspective
No full textThe recreational vehicle (RV) rental market is growing steadily. Indie Campers, founded in
Portugal in 2013, provides RV rental and sales services. From a revenue management
perspective, the goal of this project was to enhance Indie Campers’ online booking experience
and ancillary product strategies for the rental business unit. This optimization aimed to elevate
Indie Campers’ e-commerce capabilities, fostering increased revenues. Embracing Indie
Campers’ preference for an empirical testing approach, the team developed practical strategic
recommendations to refine the booking experience and the communication, pricing, and
product strategies for ancillary products, the latter including distance packages, extras, and
protection plans
Creating an evidence based, competitive market analysis for international health markets
No full textThis paper gathers evidence and builds an internationally viable business model for Thryv,
which improves the health of employees with its rewards-driven mobile application and fitness
wearable, saving companies significant productivity and health-related costs. Key findings
reveal that despite their benefits, contemporary corporate wellness programs have low
engagement rates. Existing literature and fifteen primary expert interviews attribute this lack
of use to shortcomings in user-friendliness, accessibility, social support, competition,
incentives, individualization, and data security. Thryv’s business model addresses the needs of
HR decision-makers (buyers) and employees (users) based on these seven shortcomings,
considering market conditions, competitors, and growth opportunities
The Impact of Carbon Emissions on Low-Carbon Investment Performance: Evidence From International Carbon Indexes
No full textDissertation presented as the partial requirement for obtaining a Master's degree in Statistics and Information Management, specialization in Risk Analysis and ManagementIn recent years, climate change has emerged as one of the main global environmental, social,
and economic threats. The rise in the Earth's average temperature is causing species
extinctions and extreme weather events such as droughts and floods. As a result, there is
growing interest in understanding how climate risks affect investment portfolios. The purpose
of this dissertation is to enhance investors' understanding of how climate change affects
investment returns. Specifically, we determined whether low-carbon indexes present superior
risk-adjusted returns compared to carbon-intensive indexes in the USA and Europe regions,
considering the risk factors of the Jensen's Alpha, Carhart's Four-Factor Model, Fama and
French's Five-Factor Models and the Fama-French 5 Factor Model with the addition of the
Volatility factor. This study aims to contribute to the finance field by offering thorough
analyses that can guide investors in making decisions related to climate change and financial
sustainability. By analysing the carbon emissions of low-carbon indexes and comparing them
with their returns, we investigate if indexes with lower emissions achieve better returns than
those with higher emissions. For this analysis, we selected ten low-carbon indexes and four
carbon-intensive indexes from the USA and Europe. We started with an intensive literature
review to adjust our research questions, and then we conduct the analytical part of the thesis
by employing Jensen’s Alpha Model, Carhart's Four-Factor Model, Fama and French's FiveFactor Model and an extension of Fama and French's Five-Factor Model adding a Volatility
factor to control for potential variations in risk exposure between the portfolios. The results
of our study show that investing in low-carbon indexes in the USA can potentially offer more
stable returns, even if they are lower than the S&P500 market and support a less volatility
strategy. There is similarity with the European market since investing in companies with a
lower carbon footprint in Europe may not bring consistently higher returns, either when
comparing portfolios to the market indexes used. However, the results indicate that equallyweighted portfolios have lower volatility and less sensitivity to market changes, which can be
beneficial for investors who are looking to reduce risk and minimise exposure to financial
losses. Finally, sufficient evidence indicated that the inclusion of the volatility factor had a
substantial impact on the model results and on the dispersion of portfolio returns, improving
the accuracy and effectiveness of the models in analysing low-carbon and carbon-intensive
portfolios
Efeito Dos Diferentes Tipos De Fosforite Nos Superfosfatos Simples
No full textO objetivo principal deste trabalho é estudar a influência dos diferentes tipos de fosforite (argelina e marroquina) na produção dos superfosfatos simples, SSP. Em termos de custo da matéria-prima, a fosforite argelina é a mais acessível no mercado. No entanto, nas condições atuais de funcionamento da unidade fabril da SOPAC, apenas a fosforite marroquina permite obter os SSPs de maneira eficiente. Isto é, com um teor de fósforo total em volta dos 18%(m/m), o que implica uma conversão do fósforo em volta dos 99%. Por outro lado, estudos na literatura indicam que a qualidade dos SSPs assim como a conversão do seu processo de produção é amplamente afetada pela granulometria da fosforite usada, que por sua vez depende da composição da fosforite sobretudo o teor de impurezas.
O primeiro estudo consistiu na determinação da composição química da fosforite marroquina e argelina por espectrofotometria de fluxo segmentado e ICP (Inductionly Coupled Plasma), verificando-se então que tanto a fosforite marroquina como a fosforite argelina possuem o mesmo teor de P2O5 total cerca de 31.75% variando apenas o teor de impurezas, a fosforite argelina possuí um teor de impurezas em catiões metálicos mais elevados que a marroquina.
No segundo estudo demonstrou-se que o grau de moenda da fosforite marroquina é melhor que o da argelina, devido aos altos níveis de impurezas na fosforite argelina, nomeadamente, um teor de potássio 60% superior, um teor de ferro 23% superior e de magnésio superior de 40% relativamente a fosforite marroquina. Em sequência, foi igualmente investigado o impacto das moagens 1,2,4,5 (M1-M5) no grau de moenda. Para as duas fosforites observou-se que apenas a moagem M4 permite obter uma granulometria acima dos 70% (m/m) de retidos no peneiro abaixo de 0.075mm (meta estabelecida).
No terceiro estudo, foi demonstrado, que usando a fosforite argelina é igualmente possível produzir SSP com bons níveis de conversão entre 86-88%, usando especialmente a moagem M4, com ácido sulfúrico concentrado a 72%. Para tal seria necessário um tempo de residência maior e por conseguinte um investimento suplementar num reator de maior volume.The main objective of this work is to study the influence of different types of phosphorite (Algerian and Moroccan) on the production of single superphosphates (SSPs). In terms of cost, the Algerian phosphorite is the most affordable. However, with the SOPAC’s current operating conditions, only the Moroccan phosphorite produces SSPs efficiently, with a total phosphorus content of 18% (m/m), which implies a phosphorus conversion of 99%. On the other hand, studies in the literature indicate that the quality of SSPs as well as its production conversion is largely affected by the phosphorite particle size, which in turn depends on the phosphorite composition especially the impurity content.
The first study focused in determining the chemical composition for both phosphorites with the help of segmented flow spectrophotometry and ICP (Inductionly Coupled Plasma) methods.
Where it was verified that both the Moroccan phosphorite and Algerian phosphorite have the same total P2O5 content, around 31.75%, varying the impurity content only. The Algerian phosphorite was found to have a higher content of impurities in metal cations.
The second study showed that the grinding degree of Moroccan phosphorite is better than that of the Algerian one, due to the high level of impurities in Algerian phosphorite, namely 60% higher potassium content, 23% higher iron content and over 40% higher magnesium content. The impact of the mills 1,2,4,5 (M1-M2-M4-M5) on the degree of grinding was also investigated. For both phosphorites, it was observed that only the M4 mill gives a particle size above 70% (m/m) retained on the sieve below 0.075mm (target).
In the third study, it was shown that using the Algerian phosphorite it is also possible to produce SSP with good conversion levels (86-88%), especially using the M4 grinding mil with 72% concentrated sulfuric acid. This would require a longer residence time and therefore an additional investment on a larger reactor
Startups- performance during recessions: evidence from sumup-s merchants
No full textRecent studies demonstrate that the attractiveness of entering self-employment in opposition
to unemployment outweighs the difficulty of running a business through economic downturns.
However, little research has been done on whether startups can grow during recessions and
whether B2B or B2C businesses do better then. This paper addresses these questions by
employing data on 1,252 SumUp’s merchants operating in Europe between January 2018 and
October 2022. I establish three main findings. First, ceteris paribus, B2B merchants enjoy
higher income. Second, not B2B but B2C merchants are better off in post-COVID-19. Third,
COVID-19 negatively impacted revenues, thus rejecting my first hypothesi
Machine Learning Approach to Risk-Adjusted Excess Return Classification
No full textProject Work presented as the partial requirement for obtaining a Master's degree in Data Science and Advanced Analytics, specialization in Business AnalyticsThe use of Machine Learning to develop investment strategies has been increasing in recent years, as investors and financial institutions seek new ways to gain a competitive advantage. This project proposes a Machine Learning approach for stock market investment, classifying assets as outperformers or underperformers based on their future quarterly risk-adjusted returns. Two targets are created using different thresholds: 0% and 15%. The input data includes both Fundamental Data and Technical Indicators, and four different models are tested: Logistic Regression, Decision Tree, Light Gradient Boosting, and Neural Networks. The models are evaluated using Machine Learning metrics such as AUC, Precision, Accuracy, and Recall, as well as economic metrics like the Sharpe Ratio. Validation is performed using Stratified 10-Fold cross-validation, and testing is conducted using a sequential holdout method. The training set, used for Stratified 10-Fold, ranges from 2004 to 2017, while the test set spans from 2018 to 2022. Feature selection techniques, namely Mutual Information and LASSO, are employed to determine the relevant features, and a third subset is created using PCA for dimensional reduction. In terms of results, for Target 0, the Neural Network outperforms other models with a precision of 0.5193 when considering the entire sample. However, when focusing on the observations with the highest probability of being outperformers, the Light Gradient Boosting model achieves a precision of 0.571. For Target 15, the Logistic Regression exhibits the highest precision of 0.2293 when considering the entire sample, whereas the Light Gradient Boosting model attains the highest precision of 0.3290 for the top probability observations. Both models are compared to a benchmark that classifies all assets in the sample as outperformers
Neobank’s Individual Performance: The impact of Trust and Financial Literacy
No full textDissertation presented as the partial requirement for obtaining a Master's degree in Information Management, specialization in Information Systems and Technologies ManagementFintech has rapidly grown in the past decade, disrupting the traditional banking sector, and providing a user-focused, digital only experience. This study explores the effect of neobanks on individual performance, through the combination of the IS Success model with trust and financial literacy. We collected data from 202 neobank users, through an online survey, and analysed it using structural equation modelling (SEM). Our findings reveal that use, user satisfaction, and trust in neobanking increase individual performance, and that both trust and financial literacy positively influence the use of virtual banks and their user’s satisfaction. By combining the DeLone & McLean model with trust and financial literacy, we propose several practical and theoretical implications, thereby contributing to the understanding of post-adoption user behaviour