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Mesothelioma: a systemic therapy clinical trials snapshot

Systemic therapy targets in mesothelioma.

Recent changes to clinical practice have made modest improvements in 1– 2-year survival, but longer-term survival remains unchanged, and durable benefit is very rare.

Combining immunotherapy with chemotherapy, particularly with novel bispecific agents, may result in more therapeutic modalities being administered together in the first-line setting. The current evidence for second-line treatments is sparse.

New targeted-therapy strategies are promising. Early-phase clinical trials are showing signals of efficacy in mesotheliomas harboring MTAP loss or inactivation of the Hippo pathway.

Further studies will be needed to robustly confirm clinical benefit. sciencenewshighlights ScienceMission https://sciencemission.com/Mesothelioma

Mesothelioma is a rare cancer that has seen few incremental improvements in survival over the past two decades. However, a significantly improved understanding of the underlying biology has led to new therapeutic advances with the potential to improve clinical outcomes. In this review, we take a snapshot of the current systemic therapy research landscape, with our goal to forecast the trajectory of drug development for mesothelioma over the next half-decade. In our current census, we identify 106 active trials including systemic therapies: 20 (19%) are molecularly targeted, 26 (25%) include immunomodulation, and 12 (11%) combining immunotherapy with antiangiogenic therapies. Collectively, the landscape of therapeutic innovation for mesothelioma is expanding, bringing hope that improvements in life expectancy may follow.

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Molecular Markers of Blood Cell Populations Can Help Estimate Aging of the Immune System

Aging of the immune system involves functional changes in individual cell populations, in hematopoietic tissues and at the systemic level. They are mediated by factors produced by circulating cells, niche cells, and at the systemic level. Age-related alterations in the microenvironment of the bone marrow and thymus cause a decrease in the production of naive immune cells and functional immunodeficiencies. Another result of aging and reduced tissue immune surveillance is the accumulation of senescent cells. Some viral infections deplete adaptive immune cells, increasing the risk of autoimmune and immunodeficiency conditions, leading to a general degradation in the specificity and effectiveness of the immune system in old age.

Mineral and bone effects of EPT

Highlighting the potential of PTH1R receptor agonist therapy in autosomal dominant hypocalcemia type 1

https://doi.org/10.1172/JCI201759 In this Research Letter, Rajesh V. Thakker & team report on the use of Eneboparatide in mice with ADH1, which increased serum calcium levels without increasing urine calcium.

3Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, United Kingdom.

4Endocrine Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts, USA.

5William Harvey Research Institute, London School of Medicine, Queen Mary University of London, London, United Kingdom.

Advancements in organoid models emulating metastatic niches

Metastatic niche in organoid models.

The mortality rate of cancer patients remains high, mainly due to the lack of metastasis-tailored treatments, highlighting the need for alternative experimental approaches that capture metastatic development in a human context.

Human-induced pluripotent stem cell derived organoids cocultured with cancer cells (‘chimeroids’) have the potential to emulate aspects of colonized organ specific microenvironments and offer an alternative platform for target identification and drug discovery, as these models are amenable to scalable genetic and chemical perturbation screens.

Conceptually, organoid models have progressed from epithelial-only organoids to multilineage, niche enriched systems incorporating stromal, vascular, and tissue-resident immune components, thereby bringing in vitro models closer to organ-specific metastatic microenvironments.

Yet no single organoid model fully recapitulates the entire complexity of an organ in vivo; thus, model selection must be driven by the specific scientific question, ensuring that the relevant stage of metastatic development and organ microenvironment are appropriately represented. ScienceMission sciencenewshighlights https://sciencemission.com/organoid-models-emulating-metastatic-niches

Metastases cause most cancer-related deaths, underscoring the need for therapies targeting metastatic stages, including the tumor microenvironment. Yet translating biological insights into treatments remains difficult. Preclinical metastasis research largely relies on rodent models, which have species-specific limitations and are incompatible with large-scale perturbation screens in a human context. Human organoids aim to emulate organ microenvironments in vitro and, when cocultured with cancer cells, can provide complementary models. These ‘chimeroids’ may enable scalable studies of cancer–microenvironment interactions and support genetic and pharmacological screens to discover new targets, offering insights into the final, often lethal step of metastasis—tissue colonization.

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Effects of Exercise and Intensive Vascular Risk Reduction on Cognitive Function in Older Adults: A Randomized Clinical Trial

In this multicenter randomized clinical trial, 24 months of moderate to vigorous aerobic exercise, intensive pharmacological reduction of blood pressure and serum LDL cholesterol, or the combination of these interventions did not significantly improve global cognitive function compared to usual care in older adults with hypertension and either family history of dementia or subjective cognitive decline.

Exercise and intensive vascular risk reduction each improved cardiovascular parameters, but no group differences were observed for changes in the Preclinical Alzheimer Cognitive Composite or NIH Toolbox Cognition Battery scores.

Question Can exercise, intensive pharmacological reduction of blood pressure (BP) and serum low-density lipoprotein cholesterol (LDL-C), or the combination of these interventions improve cognitive function in older adults with family history of dementia and/or self-reported subjective cognitive decline?

Findings In this randomized clinical trial of 513 participants, moderate to vigorous aerobic exercise training, intensive pharmacological lowering of BP and serum LDL-C, or both did not result in statistically significant differences in improvements in global cognitive function over 24 months.

Meaning The findings do not provide evidence in support of exercise, intensive reduction of BP and serum LDL-C, or both for improving cognitive function in older adults with family history of dementia and/or self-reported subjective cognitive decline.

Rebuilding the bridge: Functional AVN cells for cardiac repair

Directing the differentiation of human pluripotent stem cells into atrioventricular node-like cells is a critical strategy for restoring atrioventricular node dysfunction in patients. In this issue, Lohbihler et al. define a BMP2-driven protocol to engineer functional conduction bridges that recapitulate the heart’s native “gatekeeper” properties in vivo.

Targeting metabolism to combat anticancer and antibacterial drug resistance

Combating anticancer and antibacterial drug resistance by metabolic targeting.

Bacteria and cancer cells activate defense mechanisms driven by central carbon and amino acid metabolism to overcome drug-induced stress.

Drug tolerance and persistence are driven by a dormant state in bacteria, whereas cancer cells upregulate energy metabolism to withstand prolonged drug exposure.

Biofilms, granulomas, and the tumor microenvironment share hypoxic and acidic conditions, where cells rely on anaerobic and lipid metabolism for survival.

Macrophage immunometabolism influences disease progression in tuberculosis and cancer. Common approaches for overcoming drug resistance include blocking metabolic targets that enhance drug lethality and synergistic drug combinations.

Drug repurposing, dietary interventions, and immunotherapy have shown use in cancer, but their antibacterial potential remains underexplored. sciencenewshighlights ScienceMission https://sciencemission.com/Targeting-metabolism-to-combat-anticancer

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Restoring mitochondrial function in dendritic cells to treat cancer

To counteract this effect, researchers introduced dendritic cells with high mitochondrial activity into tumors in preclinical mouse models, restoring immunogenic activity and improving tumor control.

Immunotherapies for cancer, such as immune checkpoint blockade, have greatly improved care for many malignancies, but have not been successful in all cancers. To determine if their findings could help make immunotherapy more effective in tumor-bearing mice, the investigators compared the therapeutic effects of administering dendritic cells with high mitochondrial activity in combination with immune checkpoint blockade with those of either treatment alone.

“We saw the most pronounced therapeutic effect in mice treated with the combination of dendritic cells that had high mitochondrial activity and immune checkpoint blockade,” said co-first author. “Those combinations synergistically slowed or stopped tumor growth and extended survival far more than either treatment alone.”

To test one combination therapy’s long-term effects, the researchers exposed treated mice to a new tumor months later. Those mice also stopped the new tumor’s growth, indicating durable, long-term immune memory was successfully established.

To better understand the relationship between mitochondrial function and dendritic cells, the researchers examined key metabolic pathways affected by the tumor microenvironment. They identified a signaling axis composed of two proteins, OPA1 and NRF1, that regulate communication between mitochondria and the nucleus. Their expression was greatly downregulated in dendritic cells during tumor progression. Within tumors, that circuit’s downregulation acts as a metabolic switch, in effect telling the cell that it is in an energy crisis, leading dendritic cells to shut down their nonessential functions, including immunogenic activity. Science Mission sciencenewshighlights.

Scientists have discovered how tumors disable immune “gatekeeper” cells that alert the rest of the immune system to the presence of cancer — and how restoring their energy production can improve immunotherapy. Dendritic cells activate the cytotoxic immune cells that destroy cancer. The researchers found that tumors reduce dendritic cell function by decreasing their mitochondrial fitness, thus preventing formation of the anticancer immune response.

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A new era in childhood obesity

Childhood obesity!

Obesity associated with the melanocortin system can be diagnosed in childhood, including both monogenic and syndromic forms.

Genetic obesity is characterized by early onset and extreme hyperphagia, although there is no precise definition for these features.

Numerous polymalformative syndromes include obesity among their main phenotypic traits. Among these are ciliopathies, in which alterations in the neuronal ciliary system can disrupt hypothalamic proopiomelanocortin neuron signaling, helping to explain the hyperphagia and obesity frequently observed in some of these disorders.

Pharmacological treatment of patients with impairment of the leptin– melanocortin pathway can be classified into specific and nonspecific treatments.

The use of these therapies is expanding to new indications, and additional treatments are under clinical investigation for both monogenic and polygenic obesity sciencenewshighlights ScienceMission https://sciencemission.com/childhood-obesity-19506

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Less is more: Reducing zinc to boost derived islet function and survival

Less is more: Reducing zinc to boost stem cell-derived islet function and survival.

Zinc is required for insulin packaging into secretory granules, yet reduced zinc transporter activity paradoxically enhances beta cell function. In this issue, Wang et al. show that pharmacologic inhibition of zinc transport in stem cell-derived islets activates AMPK signaling and improves maturation, hypoxia resistance, VEGFA expression, and graft performance.

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