Simultaneous Determination of Methylated Nucleosides by HILIC-MS/MS Revealed Their Alterations in Urine from Breast Cancer Patients.

RNA methylation plays a vital role in the pathogenesis of a variety of diseases including cancer, and aberrant levels of modified nucleosides in RNA were revealed to be related to cancer. Urine is a favored source for biomarker discovery due to the non-invasion to patients. Herein, we developed a sensitive hydrophilic interaction liquid chromatography tandem mass spectrometry (HILIC-MS/MS) method combined with stable isotope dilution for accurate quantification of methylated nucleosides in human urine. With this method, we successfully quantified ten methylated nucleosides in urine samples collected from healthy controls and breast cancer patients. We found N6-methyladenosine (m6A), 2'-O-methyladenosine (Am), N1-methyladenosine (m1A), N6,2'-O-dimethyladenosine (m6Am), N1-methylguanosine (m1G), 2'-O-methylguanosine (Gm), 5-methylcytidine (m5C) and 2'-O-methylcytidine (Cm) were all decreased in early-stage breast cancer patients, and a nomogram prediction model was constructed. Locally advanced breast cancer patients exhibited elevated levels of urinary 2'-O-methylated nucleosides in comparison to early-stage breast cancer patients. Together, we developed a robust method for the simultaneous determination of methylated nucleosides in human urine, and the results revealed an association between the contents of urinary methylated nucleosides and the occurrence of breast cancer, which may stimulate future studies about the regulatory roles of these methylated nucleosides in the initiation and progression of breast cancer.

Oxidatively Damaged Nucleic Acid: Linking Diabetes and Cancer.

Significance: Our current knowledge of the mechanism between diabetes and cancer is limited. Oxidatively damaged nucleic acid is considered a critical factor to explore the connections between these two diseases. Recent Advances: The link between diabetes mellitus and cancer has attracted increasing attention in recent years. Emerging evidence supports that oxidatively damaged nucleic acid caused by an imbalance between reactive oxygen species generation and elimination is a bridge connecting diabetes and cancer. 8-Oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydroguanosine assume important roles as biomarkers in assessing the relationship between oxidatively damaged nucleic acid and cancer. Critical Issues: The consequences of diabetes are extensive and may lead to the occurrence of cancer by influencing a combination of factors. At present, there is no direct evidence that diabetes causes cancer by affecting a single factor. Furthermore, the difficulty in controlling variables and differences in detection methods lead to poor reliability and repeatability of results, and there are no clear cutoff values for biomarkers to indicate cancer risk. Future Directions: A better understanding of connections as well as mechanisms between diabetes and cancer is still needed. Both diabetes and cancer are currently intractable diseases. Further exploration of the specific mechanism of oxidatively damaged nucleic acid in the connection between diabetes and cancer is urgently needed. In the future, it is necessary to further take oxidatively damaged nucleic acid as an entry point to provide new ideas for the diagnosis and treatment of diabetes and cancer. Experimental drugs targeting the repair process of oxidatively generated damage require an extensive preclinical evaluation and could ultimately provide new treatment strategies for these diseases. Antioxid. Redox Signal. 37, 1153-1167.

Determination of adenosine and its modifications in urine and plasma from breast cancer patients by hydrophilic interaction liquid chromatography-tandem mass spectrometry.

RNA modifications have been revealed to be essential in many biological activities, and their disorders are associated with various human diseases, including cancers. 2'-O-methyladenosine (Am), N1-methyladenosine (m1A), N6-methyladenosine (m6A), N6,2'-O-dimethyladenosine (m6Am) and N6,N6-dimethyladenosine (m62A) are important adenosine (A) modifications. The noninvasive collection of urine samples and the diverse contents of metabolites in plasma make them favored biofluids for biomarkers discovery. In this work, we established a hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) method to quantify these six nucleosides in urine and plasma of healthy controls and breast cancer (BC) patients. The limit of detection (LOD) for A, Am, m1A, m6A, m6Am, and m62A were 0.0025, 0.01, 0.05, 0.005, 0.005, and 0.005 nM. The results showed that the concentrations of Am, m6A, and m6Am were increased, whereas m1A was decreased in the urine of BC patients compared with the healthy controls. We also found that the level ratios of m1A/A, m6A/A, and m6Am/A were all reduced in plasma from BC patients, compared with healthy controls. Interestingly, these ratios of methylated adenosine nucleosides to adenosine in plasma could better discriminate BC patients from healthy controls, compared to the levels of these nucleosides. The present study not only suggests these modified adenosines can act as noninvasive biomarkers of BC but also will contribute to investigating the impacts of RNA methylation on the occurrence and development of BC.

A case of trichotillomania with binge eating disorder: combined with N-acetylcysteine synergistic therapy.

BACKGROUND: Obsessive-compulsive and related disorders (OCRDs) are a group of intractable and chronic mental disorders. Trichotillomania (TTM) is a common type of OCRDs characterized by repetitive hair pulling, driven by escalating tension before the action and during the attempts to resist it. Binge eating disorder (BED) is a common type of eating disorder characterized by recurrent compulsive episodes of binge eating. Both have common psychological processes (tension or impulsion) and pathological manifestations (out of control), but the pathological mechanisms are still unclear and the current clinical treatments are often unsatisfactory for these two disorders. CASE PRESENTATION: A 25-year-old woman with TTM comorbid BED came to our hospital for treatment. She had accepted systematic cognitive behavioral therapy (CBT) and also monotherapy or multidrug therapy with sertraline, fluvoxamine, bupropion, risperidone in full dosage and duration for 2 years, but all of them did not work. We treated this case with N-acetylcysteine (NAC) as a synergist on the basis of recent treatment (fluvoxamine 150 mg/day and bupropion 300 mg/day). The pathological hair plucking behavior and binge eating symptoms were both significantly and rapidly improved, and the follow-up in next 14 weeks showed that the effect was still maintained. CONCLUSION: To our knowledge, this may be the first case report of using NAC as a synergist to treat TTM comorbid BED successfully, which suggest that these two disorders may have a common pathophysiological mechanism. Moreover, NAC can be one choice as a synergistic treatment for OCRDs.

Higher baseline serum adiponectin predicts better treatment remission in patients with generalized anxiety disorder treated with escitalopram.

BACKGROUND: Generalized anxiety disorder (GAD) is partly attibuted to the dysregulation of nuero-inflammation which can be mediated by adiponectin. We conducted this study was to explore the characteristics of peripheral adiponectin and its role in predicting treatment outcome in patients with generalized anxiety disorder (GAD) treated by escitalopram or venlafaxine. METHODS: A total of 70 untreated GAD inpatients who met the diagnosis criteria of the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) were enrolled and randomly selected for treatment with escitalopram (n=36) or venlafaxine (n=34) for 8 weeks. The serum adiponectin level of GAD and healthy controls (HCs) was measured by enzyme-linked immunosorbent assay (ELISA) before treatment. Hamilton Anxiety Rating Scale (HAM-A) assessment was conducted at baseline and at 1, 2, 4, and 8 weeks after treatment respectively. Serum adiponectin levels were compared between GAD patients and HCs, as well as between remission and nonremission cases; the correlation between baseline adiponectin level and HAM-A reduction rate were also analyzed. RESULTS: The serum adiponectin levels were higher in GAD patients compared to HCs (t=2.304; P=0.023), the serum adiponectin levels were higher in remission cases compared to nonremission cases (t=2.255, P=0.027), and the receiver operating characteristic (ROC) area in predicting treatment remission was 0.652±0.066 (P=0.029). The correlation between baseline adiponectin level and HAM-A reduction rate of GAD cases treated with escitalopram and venlafaxine in the endpoint was 0.362 (P=0.030) and -0.026 (P=0.883), respectively, and the ROC area of baseline adiponectin level in predicting treatment remission was 0.72±0.086 (P=0.024) and 0.473±0.102 (P=0.469), respectively. CONCLUSIONS: Peripheral adiponectin is upregulated in GAD, and it seems higher baseline adiponectin level predicts a better treatment remission treated by escitalopram but not with venlafaxine, which suggests adiponectin maybe a potential key biomarker in Chinese GAD.