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%.

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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 possibilitydrugs 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 cellsa 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 stressa 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 conceptsfor 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.

These researchers discovered that the enzyme fumarate hydratase is blocked in macrophages. Macrophages are an inflammatory cell type that has been linked to a number of disorders such as lupus, arthritis, sepsis, and COVID-19.

"No one has previously linked fumarate hydratase to inflammatory macrophages, and we feel that targeting this process may treat debilitating diseases such as lupus," said Luke O'Neill, co-corresponding author of the paper and professor of biochemistry at Trinity College Dublin. Lupus is a nasty autoimmune disease that damages multiple parts of the body, including the skin, kidneys, and joints.

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The most prevalent kind of lupus and autoimmune disease is systemic lupus erythematosus (SLE), in which the immune system attacks its own tissues, producing extensive inflammation and tissue destruction in the afflicted organs. It affects the joints, the skin, the brain, the lungs, the kidneys, and the blood vessels. Patients have symptoms such as fatigue, skin rashes, fevers, and joint discomfort or swelling. For some people, flares of SLE symptoms may occur often, sometimes even years apart, and then disappear at other times (called remission). Some people, on the other hand, have SLE flares more regularly throughout their lives. SLE also causes sun sensitivity, mouth ulcers, arthritis, lung issues, heart problems, renal problems, seizures, psychosis, and blood cell and immunological abnormalities. The causes of SLE are unclear. However, it is widely assumed that environmental, genetic, and hormonal factors are involved. SLE may vary in severity from mild to life-threatening.

In models of sepsis, it was shown that fumarate hydratase was inhibited. Sepsis is a systemic inflammatory condition that may develop as a result of bacterial or viral infections, and it often results in fatalities. Similarly, there is a significant decrease in the amount of the enzyme fumarate hydratase seen in blood samples taken from lupus patients. Therefore, restoring fumarate hydratase or targeting melanoma differentiation-associated protein 5 (MDA5) or toll-like receptor 7 (TLR7) in these disorders provides great potential for much-needed novel anti-inflammatory drugs, according to Professor O'Neill.

The most commonly used medications currently available, including small molecules and monoclonal antibodies, are:

?Nonsteroidal anti-inflammatory drugs (NSAIDs) like naproxen sodium (Aleve) and ibuprofen (Advil, Motrin IB, and others) can be used to treat lupus-related pain, edema, and fever.
?Antimalarial drugs, such as hydroxychloroquine (Plaquenil), have an effect on the immune system and can reduce the risk of lupus flares.
?Corticosteroids. Prednisone and other corticosteroids can alleviate the inflammation caused by lupus.
?Immunosuppressants. In severe cases of lupus, immunosuppressive drugs are beneficial. These drugs include azathioprine (Imuran, Azasan), mycophenolate mofetil (CellCept), and methotrexate. (Trexall).
?Biologics. Intravenous administration of Belimumab (Benlysta) reduces lupus symptoms in some patients. Rituximab (Rituxan) is advantageous in cases of lupus resistance.

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Klotho, a renowned longevity factor, naturally declines with age. Previous studies have demonstrated that transgenic overexpression of Klotho or peripheral administration of the drug extends the lifespan of mice, enhances synaptic and cognitive function, and promotes neural recovery from age-related toxicity, Alzheimer's disease, and Parkinson's disease.

Moreover, people with high levels of Klotho exhibit superior cognitive performance, reduced neuropathological indicators, and a lower risk of aging and Alzheimer's disease. These findings suggest a correlation between Klotho and human brain health.

On July 3, 2023, researchers from Yale University School of Medicine and the University of California, San Francisco published a research paper in Nature Aging titled "Longevity Factor Klotho Enhances Cognition in Aged Nonhuman Primates".

The study reveals that a single injection of the longevity protein Klotho improves cognitive function in aged monkeys, presenting a potential breakthrough in translating Klotho into a therapy for restoring brain function.

While studies in mice have provided valuable insights for the development of various therapies, it is clear that mouse models are not suitable for the advancement of human cognitive therapies. Therefore, further research on animal models with more complex brain structures and functions, such as aging non-human primates (NHPs), is crucial.

In this latest study, the team investigated whether low-dose subcutaneous injections of Klotho could enhance cognitive function in aging rhesus monkeys. Compared to mice, rhesus monkeys share 93% phylogenetic similarity with humans (compared to only 70% in mice) and possess more intricate higher-order cognitive functions.

Like humans, rhesus monkeys experience age-related cognitive decline accompanied by synaptic changes, without significant neuronal loss that impairs brain regions including the hippocampus and prefrontal cortex (PFC). The PFC, responsible for executive functions such as working memory, exhibits age-induced impairments in neuronal firing, regulated protein kinase C (PKC) activity, neurotransmitter homeostasis, and structural decline in rhesus monkeys.

The primary objective of the study was to test whether a single dose of Klotho treatment could increase serum Klotho levels in rhesus monkeys to a range similar to that observed in humans throughout their lifetime. Additionally, the researchers aimed to explore whether the cognitive benefits mediated by Klotho were dose-dependent by administering higher doses of the protein to the monkeys.

Klotho exists in transmembrane protein form and circulating hormone form. This study utilized the circulating hormone form, known as alpha-klotho protein. The researchers first generated rhesus monkey Klotho protein (96% homologous to human Klotho protein) and verified its functional activity through mouse experiments. In these experiments, a dose of 10 ug/kg body weight of rhesus monkey Klotho protein enhanced synaptic remodeling and working memory in mice.

To examine the effects of Klotho on cognitive function in NHPs, the research team administered a single low dose of Klotho (10 ug/kg body weight) to 18 aged rhesus monkeys (average age 21.78 years). The results demonstrated that a single dose of Klotho improved cognitive function in aged rhesus monkeys, as evidenced by assessments of working memory and spatial memory. Notably, this improvement persisted for at least two weeks.

In contrast, higher doses of Klotho administered to aged rhesus monkeys did not yield cognitive improvement. However, mice continued to exhibit enhanced cognitive function even at higher doses of Klotho, highlighting a disparity between mice and rhesus monkeys that may be attributed to the increased complexity of brain structure and networks in rhesus monkeys.

Given that Klotho levels decline with age in humans, this study indicates that a lower dose of 10 ug/kg body weight (similar to levels at birth) of injected Klotho enhances cognitive function in older NHPs. These findings suggest that peripheral treatment or supplementation with Klotho could potentially have therapeutic effects in aging humans and contribute to the development of future interventions combating cognitive decline in the elderly.