Proteomic and metabolomic profiling of plasma predicts immune-related adverse events in older patients with advanced non-small cell lung cancer.

The clinical success of immune checkpoint inhibitors is compromised by the fact of immune-related adverse events (irAEs), especially for older patients. To identify predictive biomarkers for older patients with irAEs, we used multiplex immunoassay and flow cytometry and liquid chromatography-tandem mass spectrometry to test immune factors and plasma protein and metabolites levels in non-small cell lung cancer (NSCLC) patients. The results showed that older patients with irAEs displayed lower CD28, CD4+ T cell, and B cell and higher interleukin (IL)-10 and CCL2 levels at baseline. Besides, lower aldolase, fructose-bisphosphate B (ALDOB), higher ST6GAL1, and lower lactate/pyruvate ratio at baseline were found in older patients with irAEs. Based on metabolomic markers, predictive models were developed to distinguish patients with grade 2-4 irAEs from grade 0-1 (Area under curve, AUC = 0.831) and to distinguish patients with grade 3-4 irAEs from grade 2 (AUC = 1). Our results confirmed the predictive value of plasma metabolites for irAEs in older patients with NSCLC.

Characterization of Histone Deacetylase Mechanisms in Cancer Development.

Over decades of studies, accumulating evidence has suggested that epigenetic dysregulation is a hallmark of tumours. Post-translational modifications of histones are involved in tumour pathogenesis and development mainly by influencing a broad range of physiological processes. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are pivotal epigenetic modulators that regulate dynamic processes in the acetylation of histones at lysine residues, thereby influencing transcription of oncogenes and tumour suppressor genes. Moreover, HDACs mediate the deacetylation process of many nonhistone proteins and thus orchestrate a host of pathological processes, such as tumour pathogenesis. In this review, we elucidate the functions of HDACs in cancer.

A newly defined risk signature, consisting of three m6A RNA methylation regulators, predicts the prognosis of ovarian cancer.

N6-methyladenosine (m6A) RNA methylation, involved in cancer initiation and progression, is dynamically regulated by the m6A RNA methylation regulators. However, the expression of m6A RNA methylation regulators in ovarian cancer and their correlation with prognosis remain elusive. Here, we demonstrated that the 18 central m6A RNA methylation regulators were expressed differently between ovarian cancer (OC) and normal tissues. By applying consensus clustering, all ovarian cancer patient cases can be divided into three subgroups (cluster1/2/3) based on overall expression levels of all 18 m6A RNA methylation regulators. We systematically analyzed the prognostic value of transcription levels of 18 m6A RNA methylation regulators in ovarian cancer and found that insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), vir like m6A methyltransferase associated (VIRMA), and zinc finger CCCH-type containing 13 (ZC3H13) yield the highest scores for predicting the prognosis of ovarian cancer. Accordingly, we derived a risk signature consisting of transcription levels of these three selected m6A RNA methylation regulators as an independent prognostic marker for OC and validated our findings with data derived from a different ovarian cancer cohort. Moreover, by the Gene Set Enrichment Analysis (GSEA), we demonstrated that the three selected regulators were all correlated with pathways in cancer and WNT signaling pathways. In conclusion, m6A RNA methylation regulators are vital participants in ovarian cancer pathology; and IGF2BP1, VIRMA, and ZC3H13 mRNA levels are valuable factors for prognosis prediction and treatment strategy development.

Functions of N6-methyladenosine and its role in cancer.

N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which is the most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests that m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A is installed by m6A methyltransferases, removed by m6A demethylases and recognized by reader proteins, which regulate of RNA metabolism including translation, splicing, export, degradation and microRNA processing. Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR. In this review, we elaborate on recent advances in research of m6A enzymes. We also highlight the underlying mechanism of m6A in cancer pathogenesis and progression. Finally, we review corresponding potential targets in cancer therapy.

Concise total syntheses of (+)-strictifolione and (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one.

Concise and efficient asymmetric total syntheses of (+)-strictifolione 1 and (6R)-6-[(4R,6R)-4,6-dihydroxy-10-phenyldec-1-enyl]-5,6-dihydro-2H-pyran-2-one 2 have been achieved based on the strategic application of one-pot double allylboration and ring-closing metathesis reactions. The total syntheses proceeded in only five and seven steps, respectively, from readily available 3-butenal and represent the shortest syntheses of 1 and 2 reported to date.

Efficient and regioselective synthesis of 5-hydroxy-2-isoxazolines: versatile synthons for isoxazoles, beta-lactams, and gamma-amino alcohols.

An efficient and highly regioselective protocol was developed for the preparation of 5-hydroxy-2-isoxazolines, which have been proved to be versatile synthons for isoxazles, beta-hydroxy oximes, and gamma-amino alcohols. Beta-lactams, commonly embedded in the skeletons of bioactive natural products, were also synthesized in two steps from beta-hydroxy oximes, providing a new strategy for the synthesis of this kind of compounds.

Efficient and regioselective one-pot synthesis of 3-substituted and 3,5-disubstituted isoxazoles.

A series of 3-substituted and 3,5-disubstituted isoxazoles have been efficiently synthesized in moderate to excellent yields by the reaction of N-hydroxyl-4-toluenesulfonamide with alpha,beta-unsaturated aldehydes/ketones. This novel strategy is associated with readily available starting materials, mild conditions, high regioselectivity, and wide scope.