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In cancer immunotherapy, the spotlight has fallen on STING as a pivotal target of recent interest. Biopharmaceutical companies worldwide are vigorously developing innovative therapies targeting STING with the goal of activating immune pathways to combat cancer cells.
While these STING agonists have demonstrated promise in preclinical studies, a perplexing phenomenon has emerged in certain clinical trials. Contrary to expectations, drugs designed to activate the STING pathway have not consistently yielded the desired benefits for advanced cancer patients. For instance, a Phase 1 clinical trial assessing STING agonists reported only one out of 47 patients with advanced or metastatic cancer displaying a definitive partial response. In another Phase 1 clinical trial involving a STING agonist co-administered with a PD-1 inhibitor, the overall remission rate for advanced cancer patients hovered around 10%.
So, what accounts for the unexpected outcomes of STING agonists in the fight against cancer? In their quest for answers, researchers at the Memorial Sloan Kettering Cancer Center, in collaboration with Weill Cornell Medicine, have uncovered a counterintuitive possibility—drugs inhibiting STING activation may prove more beneficial to patients with advanced cancer than STING activators.
This revelation hinges on the nature of the STING signaling pathway itself. Within the human body, the presence of double-stranded DNA molecules in the cytoplasmic matrix serves as an early warning signal, indicating the intrusion of pathogens, the existence of cancer cells, or cell rupture. Once intracellular sensors detect cytoplasmic DNA, they activate the STING protein, which, in turn, triggers the expression of inflammation-associated genes, igniting an innate immune response that shields the body from foreign invaders and abnormal cells—a pivotal process in anti-tumor immunity.
However, the new study suggests that cancer cells disrupt the STING signaling pathway, creating an immunosuppressive tumor microenvironment. Particularly in advanced cancer stages, where cancer cells exhibit high chromosomal instability, the STING pathway remains persistently active, leading to "desensitization." This, in turn, rewires the downstream signaling pathway, inducing endoplasmic reticulum stress—a favorable environment for cancer cell metastasis.
Dr. Samuel Bakhoum, co-corresponding author of the study, analogizes this phenomenon, "think of STING signaling as a car alarm. If it rarely sounds, the loud noise will grab your attention. But if it keeps going off, you become accustomed to it and tune it out."
To understand the interactions between cancer cells and immune cells in the tumor microenvironment, another co-corresponding author, Dr. Ashley Laughney, led the team in developing a specialized computational tool named "Contact Tracing". This tool predicts cell-cell interactions and assesses how ligand-receptor interactions influence signal-receiving cells based on single-cell sequencing data.
Dr. Laughney highlights a significant discovery, "one of our most crucial findings is that altering the degree of chromosomal instability or activating STING significantly changes the response within the tumor and its surroundings."
The researchers confirmed the link between chromosomal instability-driven cancer cell metastasis and STING signaling in mouse models implanted with various tumor cells, as well as in human healthy cells and tumor samples. These findings also open the door to innovative therapeutic concepts—for advanced cancer patients with chromosomal instability, activating STING may prove ineffective due to cellular desensitization". In such cases, inhibiting STING could be a promising alternative.
In experimental settings, the researchers administered STING inhibitors to mouse models of melanoma, breast cancer, and colorectal cancer, effectively reducing metastasis driven by chromosomal instability.
Additionally, these insights suggest that by identifying tumors still capable of robust responses to STING activation, clinicians can select patients who would genuinely benefit from STING agonist therapy.
On October 2nd, the Nobel Assembly unveiled the recipients of the 2023 Nobel Prize in Physiology or Medicine: scientists Katalin Karikó and Drew Weissman. Their pioneering research in messenger ribonucleic acid (mRNA) has reshaped vaccine development, notably amid the COVID-19 pandemic. Their work has not only saved countless lives but has also alleviated the severity of cases, relieving pressure on healthcare systems and facilitating the global reopening of societies. To date, mRNA vaccines, administered over 13 billion times worldwide, have played a pivotal role in fighting the pandemic. Scientists have delved into mRNA's potential for vaccine development since the 1990s.
The laureates' work "revolutionized our comprehension of mRNA's interaction with the immune system," crucial in the swift creation of mRNA vaccines for SARS-CoV-2 during the ongoing global health crisis. These vaccines deliver the spike protein mRNA sequence into cells using lipid nanoparticles (LNPs) as carriers. This innovative method triggers protein production, activating immune cells and eliciting responses like the creation of neutralizing antibodies and antigen-specific T cells. mRNA-based SARS-CoV-2 vaccines boast rapid production and cost-effectiveness. By amplifying antigens through mRNA synthesis, high concentrations of neutralizing antibodies are achieved, enhancing vaccine efficacy.
In contrast, producing vaccines based on whole viruses or viral proteins necessitates extensive cell cultures, complicating rapid pandemic vaccine production. SARS-CoV-2 vaccine candidates underwent testing in animal models like ACE2 humanized mice, ferrets, and rhesus macaques. Exogenous mRNA corresponding to viral gene fragments enables host cells to produce viral proteins, stimulating immune responses and serving as vaccine candidates. Yet, extracellular mRNA production suffers from instability and inefficient delivery.
The laureates' research showcased that modifying extracellular mRNA's nucleotide bases could make the host "recognize" exogenous mRNA as self-mRNA. This modification reduces inflammatory reactions and boosts protein production after delivery, removing key hurdles in mRNA's clinical application. This breakthrough paves the way for agile mRNA vaccine development for infectious diseases and holds potential for delivering therapeutic proteins and treating specific cancer types.
However, mRNA is inherently unstable and prone to enzymatic degradation within the body. Another challenge lies in the potential for mRNA to trigger intense inflammatory responses, potentially harming cells and tissues. Despite skepticism and rejection, Karikó and Weissman persevered. In 2005, they published a groundbreaking paper addressing these challenges. By modifying mRNA's building blocks, nucleotides, they enhanced stability and reduced immunogenicity. Additionally, they devised a method employing lipid nanoparticles to deliver mRNA into cells, safeguarding and transporting mRNA within minuscule lipid bubbles.
Karikó and Weissman's work stands as a groundbreaking transformation in anti-SARS-CoV-2 candidates and public health, illustrating the potency of curiosity-driven science and resilience. Their achievements inspire researchers and innovators worldwide to explore mRNA technology's potential in enhancing human health and well-being.
On October 2nd, the Nobel Assembly unveiled the recipients of the 2023 Nobel Prize in Physiology or Medicine: scientists Katalin Karikó and Drew Weissman. Their pioneering research in messenger ribonucleic acid (mRNA) has reshaped vaccine development, notably amid the COVID-19 pandemic. Their work has not only saved countless lives but has also alleviated the severity of cases, relieving pressure on healthcare systems and facilitating the global reopening of societies. To date, mRNA vaccines, administered over 13 billion times worldwide, have played a pivotal role in fighting the pandemic. Scientists have delved into mRNA's potential for vaccine development since the 1990s.
The laureates' work "revolutionized our comprehension of mRNA's interaction with the immune system," crucial in the swift creation of mRNA vaccines for SARS-CoV-2 during the ongoing global health crisis. These vaccines deliver the spike protein mRNA sequence into cells using lipid nanoparticles (LNPs) as carriers. This innovative method triggers protein production, activating immune cells and eliciting responses like the creation of neutralizing antibodies and antigen-specific T cells. mRNA-based SARS-CoV-2 vaccines boast rapid production and cost-effectiveness. By amplifying antigens through mRNA synthesis, high concentrations of neutralizing antibodies are achieved, enhancing vaccine efficacy.
In contrast, producing vaccines based on whole viruses or viral proteins necessitates extensive cell cultures, complicating rapid pandemic vaccine production. SARS-CoV-2 vaccine candidates underwent testing in animal models like ACE2 humanized mice, ferrets, and rhesus macaques. Exogenous mRNA corresponding to viral gene fragments enables host cells to produce viral proteins, stimulating immune responses and serving as vaccine candidates. Yet, extracellular mRNA production suffers from instability and inefficient delivery.
The laureates' research showcased that modifying extracellular mRNA's nucleotide bases could make the host "recognize" exogenous mRNA as self-mRNA. This modification reduces inflammatory reactions and boosts protein production after delivery, removing key hurdles in mRNA's clinical application. This breakthrough paves the way for agile mRNA vaccine development for infectious diseases and holds potential for delivering therapeutic proteins and treating specific cancer types.
However, mRNA is inherently unstable and prone to enzymatic degradation within the body. Another challenge lies in the potential for mRNA to trigger intense inflammatory responses, potentially harming cells and tissues. Despite skepticism and rejection, Karikó and Weissman persevered. In 2005, they published a groundbreaking paper addressing these challenges. By modifying mRNA's building blocks, nucleotides, they enhanced stability and reduced immunogenicity. Additionally, they devised a method employing lipid nanoparticles to deliver mRNA into cells, safeguarding and transporting mRNA within minuscule lipid bubbles.
Karikó and Weissman's work stands as a groundbreaking transformation in anti-SARS-CoV-2 candidates and public health, illustrating the potency of curiosity-driven science and resilience. Their achievements inspire researchers and innovators worldwide to explore mRNA technology's potential in enhancing human health and well-being.
In cancer immunotherapy, the spotlight has fallen on STING as a pivotal target of recent interest. Biopharmaceutical companies worldwide are vigorously developing innovative therapies targeting STING with the goal of activating immune pathways to combat cancer cells.
While these STING agonists have demonstrated promise in preclinical studies, a perplexing phenomenon has emerged in certain clinical trials. Contrary to expectations, drugs designed to activate the STING pathway have not consistently yielded the desired benefits for advanced cancer patients. For instance, a Phase 1 clinical trial assessing STING agonists reported only one out of 47 patients with advanced or metastatic cancer displaying a definitive partial response. In another Phase 1 clinical trial involving a STING agonist co-administered with a PD-1 inhibitor, the overall remission rate for advanced cancer patients hovered around 10%.
So, what accounts for the unexpected outcomes of STING agonists in the fight against cancer? In their quest for answers, researchers at the Memorial Sloan Kettering Cancer Center, in collaboration with Weill Cornell Medicine, have uncovered a counterintuitive possibility—drugs inhibiting STING activation may prove more beneficial to patients with advanced cancer than STING activators.
This revelation hinges on the nature of the STING signaling pathway itself. Within the human body, the presence of double-stranded DNA molecules in the cytoplasmic matrix serves as an early warning signal, indicating the intrusion of pathogens, the existence of cancer cells, or cell rupture. Once intracellular sensors detect cytoplasmic DNA, they activate the STING protein, which, in turn, triggers the expression of inflammation-associated genes, igniting an innate immune response that shields the body from foreign invaders and abnormal cells—a pivotal process in anti-tumor immunity.
However, the new study suggests that cancer cells disrupt the STING signaling pathway, creating an immunosuppressive tumor microenvironment. Particularly in advanced cancer stages, where cancer cells exhibit high chromosomal instability, the STING pathway remains persistently active, leading to "desensitization." This, in turn, rewires the downstream signaling pathway, inducing endoplasmic reticulum stress—a favorable environment for cancer cell metastasis.
Dr. Samuel Bakhoum, co-corresponding author of the study, analogizes this phenomenon, "think of STING signaling as a car alarm. If it rarely sounds, the loud noise will grab your attention. But if it keeps going off, you become accustomed to it and tune it out."
To understand the interactions between cancer cells and immune cells in the tumor microenvironment, another co-corresponding author, Dr. Ashley Laughney, led the team in developing a specialized computational tool named "Contact Tracing". This tool predicts cell-cell interactions and assesses how ligand-receptor interactions influence signal-receiving cells based on single-cell sequencing data.
Dr. Laughney highlights a significant discovery, "one of our most crucial findings is that altering the degree of chromosomal instability or activating STING significantly changes the response within the tumor and its surroundings."
The researchers confirmed the link between chromosomal instability-driven cancer cell metastasis and STING signaling in mouse models implanted with various tumor cells, as well as in human healthy cells and tumor samples. These findings also open the door to innovative therapeutic concepts—for advanced cancer patients with chromosomal instability, activating STING may prove ineffective due to cellular desensitization". In such cases, inhibiting STING could be a promising alternative.
In experimental settings, the researchers administered STING inhibitors to mouse models of melanoma, breast cancer, and colorectal cancer, effectively reducing metastasis driven by chromosomal instability.
Additionally, these insights suggest that by identifying tumors still capable of robust responses to STING activation, clinicians can select patients who would genuinely benefit from STING agonist therapy.
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