Keto reductases (AKRs) are overexpressed in a large number of human tumors and mediate resistance to cancer chemotherapeutics and antihormonal therapies. Existing drugs and new agents in development may surmount this resistance by acting as specific AKR isoforms or AKR pan-inhibitors to improve clinical outcome.
Analyses the main legal requirements in the California Consumer Protection Act (CCPA), general data protection regulation (GDPR) and the intersections between privacy laws, genomic data and smart contracts (such as fungible and non-fungible tokens (NFTs). The CCPA and GDPR laws impose several restrictions on the storing, accessing, processing and transferring of personal data. This has generated some challenges for lawyers, data processors and business enterprises engaged in blockchain offerings, especially as they pertain to high-risk data sets such as genomic data. The technical features of NFT, distributed storage and wallets to trace and govern genomic (DNA) data sets will allow data donors to establish digital ownership and control in line with privacy laws using ‘programmable privacy smart contracts’. To be legally compliant, the design of blockchain value propositions should include privacy-by-design capabilities in the smart contract coding language itself. This article describes three domains (privacy laws, genomics and NFTs) and begins to explore how data engineers can address the challenges of coding privacy laws, the legal requirements into smart contracts. This current approach focuses on NFTs and genomic data requirements which include the selection of genetic metadata borrowing from developing ERC specifications and their programming logic. Programmable privacy is a unique way to write and design computer code, which can automatically check the legal compliance of the smart contract in a trust-less and decentralised way. We exemplify the approach by describing the conceptual value proposition, privacy-preserving genomic data platform.
The era of transformation powered by digitization, improvements in information and communication technology, machine learning, robotics and artificial intelligence is upon us. Today, we are able to solve complex problems with the aid of technology. That notwithstanding, animal populations globally are under threat, with the extinction of species taking place at a far accelerated pace than can be reversed, thus making wildlife conservation a critical issue of our time. Along with wildlife extinction currently underway, there remains a chronic financial shortage for wildlife conservation and the funding shortfall is expanding annually. This research contends that blockchain, the technology underpinning cryptocurrencies such as Bitcoin can be utilized as a catalyst by the development of cryptowildlife nonfungible tokens (NFTs), which are provably scarce, unique and programmable digital wildlife collectible assets. These could be used to finance wildlife conservation as a supplementary source of revenue.
Human aldo-keto reductases (AKR) of the 1A, 1B, 1C and 1D subfamilies are involved in the pre-receptor regulation of nuclear (steroid hormone and orphan) receptors by regulating the local concentrations of their lipophilic ligands. AKR1C3 is one of the most interesting isoforms. It was cloned from human prostate and the recombinant protein was found to function as a 3-, 17- and 20-ketosteroid reductase with a preference for the conversion of Δ4-androstene-3,17- dione to testosterone implicating this enzyme in the local production of active androgens within the prostate. Using a validated isoform specific real-time RT-PCR procedure the AKR1C3 transcript was shown to be more abundant in primary cultures of epithelial cells than stromal cells, and its expression in stromal cells increased with benign and malignant disease. Using a validated isoform specific monoclonal Ab, AKR1C3 protein expression was also detected in prostate epithelial cells by immunoblot analysis.
Immunohistochemical staining of prostate tissue showed that AKR1C3 was expressed in adenocarcinoma and surprisingly high expression was observed in the endothelial cells. These cells are a rich source of prostaglandin G/H synthase 2 (COX-2) and
vasoactive prostaglandins (PG) and thus the ability of recombinant AKR1C enzymes to act as PGF synthases was compared. AKR1C3 had the highest catalytic efficiency (kcat/Km) for the 11-ketoreduction of PGD2 to yield 9α,11β-PGF2 raising the prospect that AKR1C3 may govern ligand access to peroxisome proliferator activated receptor (PPARγ). Activation of PPARγ is often a pro-apoptotic signal and/or leads to terminal differentiation, while 9α,11β- PGF2 is a pro-proliferative signal. AKR1C3 is potently inhibited by non-steroidal anti- inflammatory drugs suggesting that the cancer chemopreventive properties of these agents may be mediated either by inhibition of AKR1C3 or COX. To discriminate between these effects we developed potent AKR1C inhibitors based on N-phenylanthranilic acids that do not inhibit COX-1 or COX-2. These compounds can now be used to determine the role of AKR1C3 in producing two proliferative signals in the prostate namely testosterone and 9α,11β-PGF2.
The aldo-keto reductase (AKR) superfamily consists of over150 protein members sharing
similar structure and enzymaticactivities. To date, 13 human AKRs have been identified,
andthey participate in xenobiotic detoxification, biosynthesis andmetabolism. Increasing
evidence suggests the involvement ofhuman AKR proteins in cancer development,
progressionand treatment. Some proteins demonstrate multiple function-al features in
addition to being a reductase for carbonylgroups. This review article discusses the most
recent progressmade in the study of humans AKRs.
Cryptocurrency is a type of digital currency which is fully based on cryptographic methods. It also maintains the features of traditional currency but without the approval of any authority. Cryptocurrency has become famous due to having its new features in its own which is now known as its trends.
NFT- Non- Fungible Tokens and Libraries.pdfNazishTariq4
Aim to help information professionals understand the foundational concepts of this technology and how these are related to libraries so that they can evolve services alongside it.
This column will define what a non-fungible tokens (NFT) is, explore the relevant trends impacting its development and examine how it intersects with the traditional roles of the library. NFTs represent a new and growing technology that intersects with many of the same concepts that are core to librarianship. Libraries are community institutions that engender widespread trust, whereas NFTs are built atop cryptocurrency that seeks to enable anonymous peer-to-peer interactions.
Ads for blockchain, NFTs and cryptocurrencies like Bitcoin seem to be everywhere. Crypto technologies are being promoted as a replacement for banks; a new way to buy art; the next big investment opportunity, and an essential part of the metaverse.
The crypto industry had a fantastic year in 2021. The industry experienced a surge in almost every aspect - from Bitcoin and Ethereum reaching new all-time highs to the mainstream adoption of Non-Fungible Tokens (NFTs).
Analyses the main legal requirements in the California Consumer Protection Act (CCPA), general data protection regulation (GDPR) and the intersections between privacy laws, genomic data and smart contracts (such as fungible and non-fungible tokens (NFTs). The CCPA and GDPR laws impose several restrictions on the storing, accessing, processing and transferring of personal data. This has generated some challenges for lawyers, data processors and business enterprises engaged in blockchain offerings, especially as they pertain to high-risk data sets such as genomic data. The technical features of NFT, distributed storage and wallets to trace and govern genomic (DNA) data sets will allow data donors to establish digital ownership and control in line with privacy laws using ‘programmable privacy smart contracts’. To be legally compliant, the design of blockchain value propositions should include privacy-by-design capabilities in the smart contract coding language itself. This article describes three domains (privacy laws, genomics and NFTs) and begins to explore how data engineers can address the challenges of coding privacy laws, the legal requirements into smart contracts. This current approach focuses on NFTs and genomic data requirements which include the selection of genetic metadata borrowing from developing ERC specifications and their programming logic. Programmable privacy is a unique way to write and design computer code, which can automatically check the legal compliance of the smart contract in a trust-less and decentralised way. We exemplify the approach by describing the conceptual value proposition, privacy-preserving genomic data platform.
The era of transformation powered by digitization, improvements in information and communication technology, machine learning, robotics and artificial intelligence is upon us. Today, we are able to solve complex problems with the aid of technology. That notwithstanding, animal populations globally are under threat, with the extinction of species taking place at a far accelerated pace than can be reversed, thus making wildlife conservation a critical issue of our time. Along with wildlife extinction currently underway, there remains a chronic financial shortage for wildlife conservation and the funding shortfall is expanding annually. This research contends that blockchain, the technology underpinning cryptocurrencies such as Bitcoin can be utilized as a catalyst by the development of cryptowildlife nonfungible tokens (NFTs), which are provably scarce, unique and programmable digital wildlife collectible assets. These could be used to finance wildlife conservation as a supplementary source of revenue.
Human aldo-keto reductases (AKR) of the 1A, 1B, 1C and 1D subfamilies are involved in the pre-receptor regulation of nuclear (steroid hormone and orphan) receptors by regulating the local concentrations of their lipophilic ligands. AKR1C3 is one of the most interesting isoforms. It was cloned from human prostate and the recombinant protein was found to function as a 3-, 17- and 20-ketosteroid reductase with a preference for the conversion of Δ4-androstene-3,17- dione to testosterone implicating this enzyme in the local production of active androgens within the prostate. Using a validated isoform specific real-time RT-PCR procedure the AKR1C3 transcript was shown to be more abundant in primary cultures of epithelial cells than stromal cells, and its expression in stromal cells increased with benign and malignant disease. Using a validated isoform specific monoclonal Ab, AKR1C3 protein expression was also detected in prostate epithelial cells by immunoblot analysis.
Immunohistochemical staining of prostate tissue showed that AKR1C3 was expressed in adenocarcinoma and surprisingly high expression was observed in the endothelial cells. These cells are a rich source of prostaglandin G/H synthase 2 (COX-2) and
vasoactive prostaglandins (PG) and thus the ability of recombinant AKR1C enzymes to act as PGF synthases was compared. AKR1C3 had the highest catalytic efficiency (kcat/Km) for the 11-ketoreduction of PGD2 to yield 9α,11β-PGF2 raising the prospect that AKR1C3 may govern ligand access to peroxisome proliferator activated receptor (PPARγ). Activation of PPARγ is often a pro-apoptotic signal and/or leads to terminal differentiation, while 9α,11β- PGF2 is a pro-proliferative signal. AKR1C3 is potently inhibited by non-steroidal anti- inflammatory drugs suggesting that the cancer chemopreventive properties of these agents may be mediated either by inhibition of AKR1C3 or COX. To discriminate between these effects we developed potent AKR1C inhibitors based on N-phenylanthranilic acids that do not inhibit COX-1 or COX-2. These compounds can now be used to determine the role of AKR1C3 in producing two proliferative signals in the prostate namely testosterone and 9α,11β-PGF2.
The aldo-keto reductase (AKR) superfamily consists of over150 protein members sharing
similar structure and enzymaticactivities. To date, 13 human AKRs have been identified,
andthey participate in xenobiotic detoxification, biosynthesis andmetabolism. Increasing
evidence suggests the involvement ofhuman AKR proteins in cancer development,
progressionand treatment. Some proteins demonstrate multiple function-al features in
addition to being a reductase for carbonylgroups. This review article discusses the most
recent progressmade in the study of humans AKRs.
Cryptocurrency is a type of digital currency which is fully based on cryptographic methods. It also maintains the features of traditional currency but without the approval of any authority. Cryptocurrency has become famous due to having its new features in its own which is now known as its trends.
NFT- Non- Fungible Tokens and Libraries.pdfNazishTariq4
Aim to help information professionals understand the foundational concepts of this technology and how these are related to libraries so that they can evolve services alongside it.
This column will define what a non-fungible tokens (NFT) is, explore the relevant trends impacting its development and examine how it intersects with the traditional roles of the library. NFTs represent a new and growing technology that intersects with many of the same concepts that are core to librarianship. Libraries are community institutions that engender widespread trust, whereas NFTs are built atop cryptocurrency that seeks to enable anonymous peer-to-peer interactions.
Ads for blockchain, NFTs and cryptocurrencies like Bitcoin seem to be everywhere. Crypto technologies are being promoted as a replacement for banks; a new way to buy art; the next big investment opportunity, and an essential part of the metaverse.
The crypto industry had a fantastic year in 2021. The industry experienced a surge in almost every aspect - from Bitcoin and Ethereum reaching new all-time highs to the mainstream adoption of Non-Fungible Tokens (NFTs).
2024 State of Marketing Report – by HubspotMarius Sescu
https://www.hubspot.com/state-of-marketing
· Scaling relationships and proving ROI
· Social media is the place for search, sales, and service
· Authentic influencer partnerships fuel brand growth
· The strongest connections happen via call, click, chat, and camera.
· Time saved with AI leads to more creative work
· Seeking: A single source of truth
· TLDR; Get on social, try AI, and align your systems.
· More human marketing, powered by robots
ChatGPT is a revolutionary addition to the world since its introduction in 2022. A big shift in the sector of information gathering and processing happened because of this chatbot. What is the story of ChatGPT? How is the bot responding to prompts and generating contents? Swipe through these slides prepared by Expeed Software, a web development company regarding the development and technical intricacies of ChatGPT!
Product Design Trends in 2024 | Teenage EngineeringsPixeldarts
The realm of product design is a constantly changing environment where technology and style intersect. Every year introduces fresh challenges and exciting trends that mold the future of this captivating art form. In this piece, we delve into the significant trends set to influence the look and functionality of product design in the year 2024.
How Race, Age and Gender Shape Attitudes Towards Mental HealthThinkNow
Mental health has been in the news quite a bit lately. Dozens of U.S. states are currently suing Meta for contributing to the youth mental health crisis by inserting addictive features into their products, while the U.S. Surgeon General is touring the nation to bring awareness to the growing epidemic of loneliness and isolation. The country has endured periods of low national morale, such as in the 1970s when high inflation and the energy crisis worsened public sentiment following the Vietnam War. The current mood, however, feels different. Gallup recently reported that national mental health is at an all-time low, with few bright spots to lift spirits.
To better understand how Americans are feeling and their attitudes towards mental health in general, ThinkNow conducted a nationally representative quantitative survey of 1,500 respondents and found some interesting differences among ethnic, age and gender groups.
Technology
For example, 52% agree that technology and social media have a negative impact on mental health, but when broken out by race, 61% of Whites felt technology had a negative effect, and only 48% of Hispanics thought it did.
While technology has helped us keep in touch with friends and family in faraway places, it appears to have degraded our ability to connect in person. Staying connected online is a double-edged sword since the same news feed that brings us pictures of the grandkids and fluffy kittens also feeds us news about the wars in Israel and Ukraine, the dysfunction in Washington, the latest mass shooting and the climate crisis.
Hispanics may have a built-in defense against the isolation technology breeds, owing to their large, multigenerational households, strong social support systems, and tendency to use social media to stay connected with relatives abroad.
Age and Gender
When asked how individuals rate their mental health, men rate it higher than women by 11 percentage points, and Baby Boomers rank it highest at 83%, saying it’s good or excellent vs. 57% of Gen Z saying the same.
Gen Z spends the most amount of time on social media, so the notion that social media negatively affects mental health appears to be correlated. Unfortunately, Gen Z is also the generation that’s least comfortable discussing mental health concerns with healthcare professionals. Only 40% of them state they’re comfortable discussing their issues with a professional compared to 60% of Millennials and 65% of Boomers.
Race Affects Attitudes
As seen in previous research conducted by ThinkNow, Asian Americans lag other groups when it comes to awareness of mental health issues. Twenty-four percent of Asian Americans believe that having a mental health issue is a sign of weakness compared to the 16% average for all groups. Asians are also considerably less likely to be aware of mental health services in their communities (42% vs. 55%) and most likely to seek out information on social media (51% vs. 35%).
AI Trends in Creative Operations 2024 by Artwork Flow.pdfmarketingartwork
This article is all about what AI trends will emerge in the field of creative operations in 2024. All the marketers and brand builders should be aware of these trends for their further use and save themselves some time!
A report by thenetworkone and Kurio.
The contributing experts and agencies are (in an alphabetical order): Sylwia Rytel, Social Media Supervisor, 180heartbeats + JUNG v MATT (PL), Sharlene Jenner, Vice President - Director of Engagement Strategy, Abelson Taylor (USA), Alex Casanovas, Digital Director, Atrevia (ES), Dora Beilin, Senior Social Strategist, Barrett Hoffher (USA), Min Seo, Campaign Director, Brand New Agency (KR), Deshé M. Gully, Associate Strategist, Day One Agency (USA), Francesca Trevisan, Strategist, Different (IT), Trevor Crossman, CX and Digital Transformation Director; Olivia Hussey, Strategic Planner; Simi Srinarula, Social Media Manager, The Hallway (AUS), James Hebbert, Managing Director, Hylink (CN / UK), Mundy Álvarez, Planning Director; Pedro Rojas, Social Media Manager; Pancho González, CCO, Inbrax (CH), Oana Oprea, Head of Digital Planning, Jam Session Agency (RO), Amy Bottrill, Social Account Director, Launch (UK), Gaby Arriaga, Founder, Leonardo1452 (MX), Shantesh S Row, Creative Director, Liwa (UAE), Rajesh Mehta, Chief Strategy Officer; Dhruv Gaur, Digital Planning Lead; Leonie Mergulhao, Account Supervisor - Social Media & PR, Medulla (IN), Aurelija Plioplytė, Head of Digital & Social, Not Perfect (LI), Daiana Khaidargaliyeva, Account Manager, Osaka Labs (UK / USA), Stefanie Söhnchen, Vice President Digital, PIABO Communications (DE), Elisabeth Winiartati, Managing Consultant, Head of Global Integrated Communications; Lydia Aprina, Account Manager, Integrated Marketing and Communications; Nita Prabowo, Account Manager, Integrated Marketing and Communications; Okhi, Web Developer, PNTR Group (ID), Kei Obusan, Insights Director; Daffi Ranandi, Insights Manager, Radarr (SG), Gautam Reghunath, Co-founder & CEO, Talented (IN), Donagh Humphreys, Head of Social and Digital Innovation, THINKHOUSE (IRE), Sarah Yim, Strategy Director, Zulu Alpha Kilo (CA).
Trends In Paid Search: Navigating The Digital Landscape In 2024Search Engine Journal
The search marketing landscape is evolving rapidly with new technologies, and professionals, like you, rely on innovative paid search strategies to meet changing demands.
It’s important that you’re ready to implement new strategies in 2024.
Check this out and learn the top trends in paid search advertising that are expected to gain traction, so you can drive higher ROI more efficiently in 2024.
You’ll learn:
- The latest trends in AI and automation, and what this means for an evolving paid search ecosystem.
- New developments in privacy and data regulation.
- Emerging ad formats that are expected to make an impact next year.
Watch Sreekant Lanka from iQuanti and Irina Klein from OneMain Financial as they dive into the future of paid search and explore the trends, strategies, and technologies that will shape the search marketing landscape.
If you’re looking to assess your paid search strategy and design an industry-aligned plan for 2024, then this webinar is for you.
5 Public speaking tips from TED - Visualized summarySpeakerHub
From their humble beginnings in 1984, TED has grown into the world’s most powerful amplifier for speakers and thought-leaders to share their ideas. They have over 2,400 filmed talks (not including the 30,000+ TEDx videos) freely available online, and have hosted over 17,500 events around the world.
With over one billion views in a year, it’s no wonder that so many speakers are looking to TED for ideas on how to share their message more effectively.
The article “5 Public-Speaking Tips TED Gives Its Speakers”, by Carmine Gallo for Forbes, gives speakers five practical ways to connect with their audience, and effectively share their ideas on stage.
Whether you are gearing up to get on a TED stage yourself, or just want to master the skills that so many of their speakers possess, these tips and quotes from Chris Anderson, the TED Talks Curator, will encourage you to make the most impactful impression on your audience.
See the full article and more summaries like this on SpeakerHub here: https://speakerhub.com/blog/5-presentation-tips-ted-gives-its-speakers
See the original article on Forbes here:
http://www.forbes.com/forbes/welcome/?toURL=http://www.forbes.com/sites/carminegallo/2016/05/06/5-public-speaking-tips-ted-gives-its-speakers/&refURL=&referrer=#5c07a8221d9b
ChatGPT and the Future of Work - Clark Boyd Clark Boyd
Everyone is in agreement that ChatGPT (and other generative AI tools) will shape the future of work. Yet there is little consensus on exactly how, when, and to what extent this technology will change our world.
Businesses that extract maximum value from ChatGPT will use it as a collaborative tool for everything from brainstorming to technical maintenance.
For individuals, now is the time to pinpoint the skills the future professional will need to thrive in the AI age.
Check out this presentation to understand what ChatGPT is, how it will shape the future of work, and how you can prepare to take advantage.
A brief introduction to DataScience with explaining of the concepts, algorithms, machine learning, supervised and unsupervised learning, clustering, statistics, data preprocessing, real-world applications etc.
It's part of a Data Science Corner Campaign where I will be discussing the fundamentals of DataScience, AIML, Statistics etc.
Time Management & Productivity - Best PracticesVit Horky
Here's my presentation on by proven best practices how to manage your work time effectively and how to improve your productivity. It includes practical tips and how to use tools such as Slack, Google Apps, Hubspot, Google Calendar, Gmail and others.
The six step guide to practical project managementMindGenius
The six step guide to practical project management
If you think managing projects is too difficult, think again.
We’ve stripped back project management processes to the
basics – to make it quicker and easier, without sacrificing
the vital ingredients for success.
“If you’re looking for some real-world guidance, then The Six Step Guide to Practical Project Management will help.”
Dr Andrew Makar, Tactical Project Management
2024 State of Marketing Report – by HubspotMarius Sescu
https://www.hubspot.com/state-of-marketing
· Scaling relationships and proving ROI
· Social media is the place for search, sales, and service
· Authentic influencer partnerships fuel brand growth
· The strongest connections happen via call, click, chat, and camera.
· Time saved with AI leads to more creative work
· Seeking: A single source of truth
· TLDR; Get on social, try AI, and align your systems.
· More human marketing, powered by robots
ChatGPT is a revolutionary addition to the world since its introduction in 2022. A big shift in the sector of information gathering and processing happened because of this chatbot. What is the story of ChatGPT? How is the bot responding to prompts and generating contents? Swipe through these slides prepared by Expeed Software, a web development company regarding the development and technical intricacies of ChatGPT!
Product Design Trends in 2024 | Teenage EngineeringsPixeldarts
The realm of product design is a constantly changing environment where technology and style intersect. Every year introduces fresh challenges and exciting trends that mold the future of this captivating art form. In this piece, we delve into the significant trends set to influence the look and functionality of product design in the year 2024.
How Race, Age and Gender Shape Attitudes Towards Mental HealthThinkNow
Mental health has been in the news quite a bit lately. Dozens of U.S. states are currently suing Meta for contributing to the youth mental health crisis by inserting addictive features into their products, while the U.S. Surgeon General is touring the nation to bring awareness to the growing epidemic of loneliness and isolation. The country has endured periods of low national morale, such as in the 1970s when high inflation and the energy crisis worsened public sentiment following the Vietnam War. The current mood, however, feels different. Gallup recently reported that national mental health is at an all-time low, with few bright spots to lift spirits.
To better understand how Americans are feeling and their attitudes towards mental health in general, ThinkNow conducted a nationally representative quantitative survey of 1,500 respondents and found some interesting differences among ethnic, age and gender groups.
Technology
For example, 52% agree that technology and social media have a negative impact on mental health, but when broken out by race, 61% of Whites felt technology had a negative effect, and only 48% of Hispanics thought it did.
While technology has helped us keep in touch with friends and family in faraway places, it appears to have degraded our ability to connect in person. Staying connected online is a double-edged sword since the same news feed that brings us pictures of the grandkids and fluffy kittens also feeds us news about the wars in Israel and Ukraine, the dysfunction in Washington, the latest mass shooting and the climate crisis.
Hispanics may have a built-in defense against the isolation technology breeds, owing to their large, multigenerational households, strong social support systems, and tendency to use social media to stay connected with relatives abroad.
Age and Gender
When asked how individuals rate their mental health, men rate it higher than women by 11 percentage points, and Baby Boomers rank it highest at 83%, saying it’s good or excellent vs. 57% of Gen Z saying the same.
Gen Z spends the most amount of time on social media, so the notion that social media negatively affects mental health appears to be correlated. Unfortunately, Gen Z is also the generation that’s least comfortable discussing mental health concerns with healthcare professionals. Only 40% of them state they’re comfortable discussing their issues with a professional compared to 60% of Millennials and 65% of Boomers.
Race Affects Attitudes
As seen in previous research conducted by ThinkNow, Asian Americans lag other groups when it comes to awareness of mental health issues. Twenty-four percent of Asian Americans believe that having a mental health issue is a sign of weakness compared to the 16% average for all groups. Asians are also considerably less likely to be aware of mental health services in their communities (42% vs. 55%) and most likely to seek out information on social media (51% vs. 35%).
AI Trends in Creative Operations 2024 by Artwork Flow.pdfmarketingartwork
This article is all about what AI trends will emerge in the field of creative operations in 2024. All the marketers and brand builders should be aware of these trends for their further use and save themselves some time!
A report by thenetworkone and Kurio.
The contributing experts and agencies are (in an alphabetical order): Sylwia Rytel, Social Media Supervisor, 180heartbeats + JUNG v MATT (PL), Sharlene Jenner, Vice President - Director of Engagement Strategy, Abelson Taylor (USA), Alex Casanovas, Digital Director, Atrevia (ES), Dora Beilin, Senior Social Strategist, Barrett Hoffher (USA), Min Seo, Campaign Director, Brand New Agency (KR), Deshé M. Gully, Associate Strategist, Day One Agency (USA), Francesca Trevisan, Strategist, Different (IT), Trevor Crossman, CX and Digital Transformation Director; Olivia Hussey, Strategic Planner; Simi Srinarula, Social Media Manager, The Hallway (AUS), James Hebbert, Managing Director, Hylink (CN / UK), Mundy Álvarez, Planning Director; Pedro Rojas, Social Media Manager; Pancho González, CCO, Inbrax (CH), Oana Oprea, Head of Digital Planning, Jam Session Agency (RO), Amy Bottrill, Social Account Director, Launch (UK), Gaby Arriaga, Founder, Leonardo1452 (MX), Shantesh S Row, Creative Director, Liwa (UAE), Rajesh Mehta, Chief Strategy Officer; Dhruv Gaur, Digital Planning Lead; Leonie Mergulhao, Account Supervisor - Social Media & PR, Medulla (IN), Aurelija Plioplytė, Head of Digital & Social, Not Perfect (LI), Daiana Khaidargaliyeva, Account Manager, Osaka Labs (UK / USA), Stefanie Söhnchen, Vice President Digital, PIABO Communications (DE), Elisabeth Winiartati, Managing Consultant, Head of Global Integrated Communications; Lydia Aprina, Account Manager, Integrated Marketing and Communications; Nita Prabowo, Account Manager, Integrated Marketing and Communications; Okhi, Web Developer, PNTR Group (ID), Kei Obusan, Insights Director; Daffi Ranandi, Insights Manager, Radarr (SG), Gautam Reghunath, Co-founder & CEO, Talented (IN), Donagh Humphreys, Head of Social and Digital Innovation, THINKHOUSE (IRE), Sarah Yim, Strategy Director, Zulu Alpha Kilo (CA).
Trends In Paid Search: Navigating The Digital Landscape In 2024Search Engine Journal
The search marketing landscape is evolving rapidly with new technologies, and professionals, like you, rely on innovative paid search strategies to meet changing demands.
It’s important that you’re ready to implement new strategies in 2024.
Check this out and learn the top trends in paid search advertising that are expected to gain traction, so you can drive higher ROI more efficiently in 2024.
You’ll learn:
- The latest trends in AI and automation, and what this means for an evolving paid search ecosystem.
- New developments in privacy and data regulation.
- Emerging ad formats that are expected to make an impact next year.
Watch Sreekant Lanka from iQuanti and Irina Klein from OneMain Financial as they dive into the future of paid search and explore the trends, strategies, and technologies that will shape the search marketing landscape.
If you’re looking to assess your paid search strategy and design an industry-aligned plan for 2024, then this webinar is for you.
5 Public speaking tips from TED - Visualized summarySpeakerHub
From their humble beginnings in 1984, TED has grown into the world’s most powerful amplifier for speakers and thought-leaders to share their ideas. They have over 2,400 filmed talks (not including the 30,000+ TEDx videos) freely available online, and have hosted over 17,500 events around the world.
With over one billion views in a year, it’s no wonder that so many speakers are looking to TED for ideas on how to share their message more effectively.
The article “5 Public-Speaking Tips TED Gives Its Speakers”, by Carmine Gallo for Forbes, gives speakers five practical ways to connect with their audience, and effectively share their ideas on stage.
Whether you are gearing up to get on a TED stage yourself, or just want to master the skills that so many of their speakers possess, these tips and quotes from Chris Anderson, the TED Talks Curator, will encourage you to make the most impactful impression on your audience.
See the full article and more summaries like this on SpeakerHub here: https://speakerhub.com/blog/5-presentation-tips-ted-gives-its-speakers
See the original article on Forbes here:
http://www.forbes.com/forbes/welcome/?toURL=http://www.forbes.com/sites/carminegallo/2016/05/06/5-public-speaking-tips-ted-gives-its-speakers/&refURL=&referrer=#5c07a8221d9b
ChatGPT and the Future of Work - Clark Boyd Clark Boyd
Everyone is in agreement that ChatGPT (and other generative AI tools) will shape the future of work. Yet there is little consensus on exactly how, when, and to what extent this technology will change our world.
Businesses that extract maximum value from ChatGPT will use it as a collaborative tool for everything from brainstorming to technical maintenance.
For individuals, now is the time to pinpoint the skills the future professional will need to thrive in the AI age.
Check out this presentation to understand what ChatGPT is, how it will shape the future of work, and how you can prepare to take advantage.
A brief introduction to DataScience with explaining of the concepts, algorithms, machine learning, supervised and unsupervised learning, clustering, statistics, data preprocessing, real-world applications etc.
It's part of a Data Science Corner Campaign where I will be discussing the fundamentals of DataScience, AIML, Statistics etc.
Time Management & Productivity - Best PracticesVit Horky
Here's my presentation on by proven best practices how to manage your work time effectively and how to improve your productivity. It includes practical tips and how to use tools such as Slack, Google Apps, Hubspot, Google Calendar, Gmail and others.
The six step guide to practical project managementMindGenius
The six step guide to practical project management
If you think managing projects is too difficult, think again.
We’ve stripped back project management processes to the
basics – to make it quicker and easier, without sacrificing
the vital ingredients for success.
“If you’re looking for some real-world guidance, then The Six Step Guide to Practical Project Management will help.”
Dr Andrew Makar, Tactical Project Management
Beginners Guide to TikTok for Search - Rachel Pearson - We are Tilt __ Bright...
Keto reductases- In cancer drug resistance.pdf
1. Keto reductases- In cancer drug resistance
Statement:
Keto reductases (AKRs) are overexpressed in a large number of human tumors and mediate
resistance to cancer chemotherapeutics and antihormonal therapies. Existing drugs and new
agents in development may surmount this resistance by acting as specific AKR isoforms or AKR
pan-inhibitors to improve clinical outcome.
Access now and get crypto quantum leap
Introduction:
Keto reductases (AKRs) catalyze the NADPH-dependent reduction of carbonyl groups to
alcohols for conjugation reactions to proceed. They are implicated in resistance to cancer
chemotherapeutic agents either because they are directly involved in their metabolism or help
eradicate the cellular stress created by these agents (e.g., reactive oxygen species and lipid
peroxides). Furthermore, this cellular stress activates the nuclear factor-erythroid 2 p45-related
factor 2 (NRF2)-Kelch-like ECH-associated protein 1 pathway. As many human AKR genes are
upregulated by the NRF2 transcription factor, this leads to a feed-forward mechanism to enhance
drug resistance. Resistance to major classes of chemotherapeutic agents (anthracyclines,
mitomycin, cis-platin, antitubulin agents, vinca alkaloids, and cyclophosphamide) occurs by this
mechanism. Human AKRs also catalyze the synthesis of androgens and estrogens and the
elimination of progestogens and are involved in hormonal-dependent malignancies. They are
upregulated by antihormonal therapy providing a second mechanism for cancer drug resistance.
Inhibitors of the NRF2 system or pan-AKR1C inhibitors offer promise to surmount cancer drug
resistance and/or synergize the effects of existing drugs.
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Involvement in drug resistance:
Keto reductases are overexpressed in a broad range of human cancers, e.g., prostate, breast,
glioma, neuroblastoma, non-small lung cancer and small cell lung cancer, colon cancer, cancer
of the small intestine, and acute myelocytic leukemia (AML) (Birtwistle et al., 2009). Tumor-
specific expression of the AKR isoforms has been observed, e.g., nonsmall cell lung cancer
(AKR1C1, AKR1C2, AKR1C3 and AKR1B10); Angulo et al., 2020), colon cancer (AKR1B10),
breast and prostate cancer (AKR1C3), and AML (AKR1C3). The abundance of AKR
overexpression has led to the proposition that they can be used as tumor biomarkers.
The AKRs are also stress response genes and respond to electrophilic and oxidative stress,
osmotic stress, and steroid hormones. They are induced by the Nuclear factor-erythroid 2 p45-
related factor 2 (NRF2) (NFE2L2)-Kelch-like ECH-associated protein 1 (KEAP1) (KEAP1)
pathway by AP-1 transcription factors, a tonictiy responsive enhancer, and are regulated by
steroid hormone receptors via steroid responsive enhancer, and are regulated by steroid hormone
receptors via steroid response elements. Since they respond to electrophilic and oxidative stress
stimuli, which are generated by chemotherapeutic agents, they are upregulated by these agents,
and this contributes to drug resistance. Because they also play a role in steroid hormone
transformation, they are involved in chemoresistance to hormone ablative therapies.
3. Stress Response and Nuclear Factor-Erythroid 2 p45-Related Factor 2
Induction of Aldo-Keto Reductases:
NRF2-KEAP1 is a master regulator of stress response genes. Under basal conditions, NRF2 is
tethered to KEAP1, which is an adaptor protein for the cullin-3. RealIy Interesting New Gene-
box protein 1 ubiquitin ligase, which targets NRF2 for ubiquitination and proteasomal
degradation. Electrophiles and reactive oxygen species (ROS) modify key cysteine residues in
KEAP1, which prevents ubiquitination of NRF2; Dinkova-Kostova et al., 2017). Newly
synthesized NRF2 can thus evade ubiquitination, translocate to the nucleus, and bind to its
heterodimeric partner small-maf on the antioxidant response element (ARE) (5′-A/G-TGA-C/G-
NNN-GC-A/G-3′) of stress response genes to increase gene transcription. AKR1C1-AKR1C3
genes contain multiple AREs (6–16 based on a consensus sequence search and a positional
matrix search) in their promoters.
Prototypic NRF2 activators such as R-sulforaphane (SFN) and the triterpenoid 1-(2-Cyano-
3,12,28-trioxooleana-1,9(11)-dien-28-yl)-1H-imidazole (CDDO) have been used as cancer
chemo-prevention agents in that they could lead to the inactivation of electrophiles that would
damage DNA and initiate cancer. The same activators could also lead to the elimination of
cytotoxic species required for the efficacy of the cancer chemotherapeutic response. Thus, the
activation of NRF2 leading to chemoresistance is considered the “dark side” of NRF2 activation.
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Studies by Ciaccio and Tew originally showed that human colon cancer cells that were resistant
to ethacrynic acid had highly elevated levels of dihydrodiol dehydrogenase; AKR1C1-AKR1C4 .
Further, Northern analysis and RNA protection studies showed that AKR1C1-AKR1C3
transcripts were upregulated by electrophilic and oxidative stress in HepG2 cells showed that
small interfering-RNA (si-RNA) for KEAP1 in human immortal keratinocytes (HaCaT) resulted
in upregulation of AKR1B10, AKR1C1/2, and AKR1C3 transcripts by reverse-transcription
polymerase chain reaction and AKR1B10 and AKR1C1/2 protein. Similarly, NFE2L2 si-RNA
resulted in downregulation of the same AKRs. In another study, it was found that KEAP1 si-
RNA resulted in upregulation of AKR1B10, AKR1C1, AKR1C2, and AKR1C3 in human breast
cancer cells at the transcript level and at the protein level as well by stable isotope labeling by
amino acids in cell culture-labeling followed by mass spectrometry. Furthermore, this
transcriptomic and proteomic analysis showed that these genes were the most highly regulated
by the NRF2-KEAP1 pathway (Agyeman et al., 2012). Recent CRISPR/Cas9 gene editing of
NFE2L2 in A549 lung adenocarcinoma cells showed that high constitutive expression of
AKR1C1, AKR1C2, and AKR1C3 was eliminated by NRF2 deletion (Murray et al., 2019b). In
A549 cells, KEAP1 is hypermethylated and mutated, leading to high levels of NRF2. It is now
known that the majority of the human AKR genes are regulated by the NRF2-KEAP1 pathway
and these data are summarized in These findings suggest that NRF2 activation would exacerbate
drug resistance mediated by AKRs. In addition, NRF2 activation can lead to an increase in GSH
biosynthesis via induction of gamma-glutamyl cysteine synthetase light chain and increase
cofactor availability for glutathione-S-transferases . Increased glutathione-S-transferase activity
can eliminate cytotoxic species generated by chemotherapeutic agents (e.g., 4-hydroxy-2-
nonenal and acrolein) by glutathione conjugation. Thus, a place exists for both AKR inhibitors
and inhibitors of NRF2 to surmount drug resistance. Examples of how AKRs mediate resistance
to major classes of chemotherapeutic drugs and antihormonal therapies follow in sections 4 and
5.
Resistance to Major cancer Chemotherapeutics:
Resistance is multifactorial and can include increased drug metabolism, e.g., induction of
CYP3A4 , changes in expression of solute uptake transporters [solute carriers (SLC)] and drug
efflux pumps, e.g.,ABC transporters (P-glycoprotein and multiple drug resistance proteins) and
increased GSH biosynthesis to increase conjugation capacity by glutathione-S-transferases and
counter oxidative stress. SLC are less studied as compared with ABC transporters, although
about 70% of cytotoxic compounds depend on SLC transporters. As uptake transporters, they
regulate influx of drugs (e.g., SLC29A1 mediates the influx of fluorouracil, SLC35A2 and
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SLC38A5 mediate the influx of cis-platin, and more than 20 SLC mediate the uptake of
methotrexate) and affect their intracellular concentrations. The role of these transporters was
identified by genetic screens against 60 different cytotoxic drugs. Downregulation of SLC genes
may prevent drug uptake, and upregulation may support higher energy and nutrition requirement
of cancer cells. Alterations in expression of a number of SLC genes has been observed in ovarian
cancer cell lines W1 and A2780 resistant to cis-platin, doxorubicin, topotecan, and paclitaxel.
Since multiple mechanisms of drug resistance can exist, treatment of resistance by targeting a
single mechanism is likely to fail since, under the selection pressure of drug treatment, the tumor
can adapt and substitute other pathways of resistance.
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Numerous studies implicate human AKRs in drug resistance to the major classes of cancer
chemotherapeutic agents: the anthracyclines (daunorubicin and doxorubicin); mitomycin; cis-
platin, methotrexate, oracin, vinca alkaloids, and cyclophosphamide. Three mechanisms may
account for the drug resistance observed: 1) involvement of AKRs in drug inactivation by
catalyzing carbonyl reduction to alcohols; 2) involvement of AKRs in the reduction of quinones
to hydroquinones (anthracyclines and mitomycin) with the concomitant production of ROS to
increase NRF2 activation and elevate AKR expression by a feed-forward mechanism; and 3)
upregulation due to the cellular stress created by drug exposure and elimination of that stress,
e.g., inactivation of 4-hydroxy-2-nonenal (4-HNE) produced as a byproduct of lipid
peroxidation. When five human recombinant AKRs were compared for the conversion of 4-
HNE to 1,4-dihydroxy-2-nonene, the enzyme with the highest catalytic efficiency for this
reaction was found to be AKR1C1. Direct evidence that these AKRs are involved in drug
resistance comes from genetic approaches, e.g., RNA interference, transfection studies, and
pharmacological inhibition of AKRs. While overexpression of the AKRs is commonly mediated
by the NRF2-KEAP1 pathway, they can also be overexpressed as part of disease pathogenesis. In
the subsections that follow, we describe the mode-of-action of each therapeutic agent, evidence
that AKRs are involved in resistance to that drug based on enzyme activity, transfection studies,
forced overexpression, RNA interference, and association studies with overexpression in cancer
cell lines. Where possible, we address the relative contribution of AKRs to the drug resistance
phenotype. The ability of AKR isoform inhibitors to reverse drug resistance and synergize the
effects of chemotherapeutic drugs are described in sections 7 and 8, respectively.
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6. Tyrosine Kinase Inhibitors:
Several tyrosine kinase inhibitors such as imatinib, nilotinib, erlotinib, and ponatinib are
currently used for the treatment of some cancers. The AKRs do not appear to be involved in
resistance to these agents. To the contrary, the tyrosine kinase inhibitor ibrutinib is an inhibitor
of AKR1C3 and can counteract anthracycline drug resistance mediated by AKR1C3 (Morell et
al., 2020). Apatinib also inhibits the NRF2 pathway which would lead to a downregulation of
AKR genes regulated by NRF2 and could surmount drug resistance to other chemotherapeutic
agents. Imatinib, nilotinib, and ponatinib are amides, while erlotinib does not contain a carbonyl
group and therefore, these compounds would not be substrates for AKRs.
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7. Conclusions:
Resistance to anticancer drugs, whether they be cancer chemotherapeutic agents or anti-hormone
therapeutics, remains a major factor limiting their use. For the former, there can also be dose-
limiting toxicity. Identification of targets that mediate resistance and the development of
inhibitors for these targets can prolong the benefit of existing agents, limit toxicity, and increase
overall survival. This review establishes the case that members of the AKR gene superfamily are
intimately involved in drug resistance and inhibitors may have a significant benefit in
surmounting resistance and increasing drug sensitivity. In some instances, a battery of AKR
genes can be involved, and thus, a balance exists between the use of isoform specific inhibitors
and pan-inhibitors. Some of these inhibitors are existing drugs (e.g., indomethacin, 6-
medroxyprogesterone acetate, flufenamic acid, purvalanol A, roscovitine, and buparlisib) and
could be used for improved outcomes and can be tested in adaptive clinical trials. In other cases
where isoform specific inhibitors have been identified from enzyme screening and efficacy in
cancer cell models has been established, more preclinical development of these agents is
required. Knowing that the AKR genes are regulated by the NRF2-KEAP1 pathway identifies
NRF2 inhibitors as another strategy to surmount drug resistance.
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