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Category: biotech/medical – Page 2,290

The genetic and cellular alterations that define cancer provide the immune system with the means to generate T cell responses that recognize and eradicate cancer cells. However, elimination of cancer by T cells is only one step in the Cancer-Immunity Cycle, which manages the delicate balance between the recognition of nonself and the prevention of autoimmunity. Identification of cancer cell T cell inhibitory signals, including PD-L1, has prompted the development of a new class of cancer immunotherapy that specifically hinders immune effector inhibition, reinvigorating and potentially expanding preexisting anticancer immune responses. The presence of suppressive factors in the tumor microenvironment may explain the limited activity observed with previous immune-based therapies and why these therapies may be more effective in combination with agents that target other steps of the cycle. Emerging clinical data suggest that cancer immunotherapy is likely to become a key part of the clinical management of cancer.

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Genetic, epidemiologic, and biochemical evidence suggests that predisposition to Alzheimer’s disease (AD) may arise from altered cholesterol metabolism, although the molecular pathways that may link cholesterol to AD phenotypes are only partially understood. Here, we perform a phenotypic screen for pTau accumulation in AD-patient iPSC-derived neurons and identify cholesteryl esters (CE), the storage product of excess cholesterol, as upstream regulators of Tau early during AD development. Using isogenic induced pluripotent stem cell (iPSC) lines carrying mutations in the cholesterol-binding domain of APP or APP null alleles, we found that while CE also regulate Aβ secretion, the effects of CE on Tau and Aβ are mediated independent pathways. Efficacy and toxicity screening in iPSC- derived astrocytes and neurons showed that allosteric activation of CYP46A1 lowers CE specifically in neurons and is well tolerated by astrocytes. These data reveal that CE independently regulate Tau and Aβ and identify a druggable CYP46A1-CE-Tau axis in AD.

Van der Kant et al. performed a repurposing drug screen in iPSC-derived AD neurons and identified compounds that reduce aberrant accumulation of phosphorylated Tau (pTau). Reduction of cholesteryl ester levels or allosteric activation of CYP46A1 by lead compounds enhanced pTau degradation independently of APP and Aβ.

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The derivation of human embryonic stem cells (hESCs) and the stunning discovery that somatic cells can be reprogrammed into human induced pluripotent stem cells (hiPSCs) holds the promise to revolutionize biomedical research and regenerative medicine. In this Review, we focus on disorders of the central nervous system and explore how advances in human pluripotent stem cells (hPSCs) coincide with evolutions in genome engineering and genomic technologies to provide realistic opportunities to tackle some of the most devastating complex disorders.

Advances in stem cell biology are paving new paths toward their use in the clinic, especially toward understanding and treating neurological and neurodegenerative disease.

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Harnessing an antitumor immune response has been a fundamental strategy in cancer immunotherapy. For over a century, efforts have primarily focused on amplifying immune activation mechanisms that are employed by humans to eliminate invaders such as viruses and bacteria. This “immune enhancement” strategy often results in rare objective responses and frequent immune-related adverse events (irAEs). However, in the last decade, cancer immunotherapies targeting the B7-H1/PD-1 pathway (anti-PD therapy), have achieved higher objective response rates in patients with much fewer irAEs.

This Perspective discusses the concept of immune normalization and how its underlying principles may help to augment, as well as design, cancer immunotherapies.

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When researchers fed mosquitoes a drug used to treat people for obesity, the insects were less interested in hunting for their next human meal ticket. Karen Hopkin reports.

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Believe it or not, mosquitoes don’t bite out of spite. Female mosquitoes of the species Aedes aegypti need the nutrients present in your plasma to ensure the proper development of their eggs. And though their thirst may seem unquenchable, the ladies actually take time to savor your blood once they’ve sipped their fill.

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Cancer cells are, in some respects, impressive: They can grow relentlessly, sidestep the aging process by becoming immortal, and evade the immune system’s persistent attacks. But in the process of acquiring such superpowers, the cells must occasionally relinquish other, more mundane skills—including the ability to produce certain nutrients.

Researchers at The Rockefeller University now announce the discovery of a rare tumor type that is unable to synthesize cholesterol, a molecule without which can’t survive.

“These cells become dependent on taking up cholesterol from their environment, and we can use this dependency to design therapies that block cholesterol uptake,” says Kivanç Birsoy, the Chapman Perelman Assistant Professor, who reports the findings in Nature.

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