Purine salvage-associated metabolites as biomarkers for early diagnosis of esophageal squamous cell carcinoma: a diagnostic model-based study.

Esophageal squamous cell carcinoma (ESCC) remains an important health concern in developing countries. Patients with advanced ESCC have a poor prognosis and survival rate, and achieving early diagnosis remains a challenge. Metabolic biomarkers are gradually gaining attention as early diagnostic biomarkers. Hence, this multicenter study comprehensively evaluated metabolism dysregulation in ESCC through an integrated research strategy to identify key metabolite biomarkers of ESCC. First, the metabolic profiles were examined in tissue and serum samples from the discovery cohort (n = 162; ESCC patients, n = 81; healthy volunteers, n = 81), and ESCC tissue-induced metabolite alterations were observed in the serum. Afterward, RNA sequencing of tissue samples (n = 46) was performed, followed by an integrated analysis of metabolomics and transcriptomics. The potential biomarkers for ESCC were further identified by censoring gene-metabolite regulatory networks. The diagnostic value of the identified biomarkers was validated in a validation cohort (n = 220), and the biological function was verified. A total of 457 dysregulated metabolites were identified in the serum, of which 36 were induced by tumor tissues. The integrated analyses revealed significant alterations in the purine salvage pathway, wherein the abundance of hypoxanthine/xanthine exhibited a positive correlation with HPRT1 expression and tumor size. A diagnostic model was developed using two purine salvage-associated metabolites. This model could accurately discriminate patients with ESCC from normal individuals, with an area under the curve (AUC) (95% confidence interval (CI): 0.680-0.843) of 0.765 in the external cohort. Hypoxanthine and HPRT1 exerted a synergistic effect in terms of promoting ESCC progression. These findings are anticipated to provide valuable support in developing novel diagnostic approaches for early ESCC and enhance our comprehension of the metabolic mechanisms underlying this disease.

Identifying plasma metabolic characteristics of major depressive disorder, bipolar disorder, and schizophrenia in adolescents.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are classified as major mental disorders and together account for the second-highest global disease burden, and half of these patients experience symptom onset in adolescence. Several studies have reported both similar and unique features regarding the risk factors and clinical symptoms of these three disorders. However, it is still unclear whether these disorders have similar or unique metabolic characteristics in adolescents. We conducted a metabolomics analysis of plasma samples from adolescent healthy controls (HCs) and patients with MDD, BD, and SCZ. We identified differentially expressed metabolites between patients and HCs. Based on the differentially expressed metabolites, correlation analysis, metabolic pathway analysis, and potential diagnostic biomarker identification were conducted for disorders and HCs. Our results showed significant changes in plasma metabolism between patients with these mental disorders and HCs; the most distinct changes were observed in SCZ patients. Moreover, the metabolic differences in BD patients shared features with those in both MDD and SCZ, although the BD metabolic profile was closer to that of MDD than to SCZ. Additionally, we identified the metabolites responsible for the similar and unique metabolic characteristics in multiple metabolic pathways. The similar significant differences among the three disorders were found in fatty acid, steroid-hormone, purine, nicotinate, glutamate, tryptophan, arginine, and proline metabolism. Interestingly, we found unique characteristics of significantly altered glycolysis, glycerophospholipid, and sphingolipid metabolism in SCZ; lysine, cysteine, and methionine metabolism in MDD and BD; and phenylalanine, tyrosine, and aspartate metabolism in SCZ and BD. Finally, we identified five panels of potential diagnostic biomarkers for MDD-HC, BD-HC, SCZ-HC, MDD-SCZ, and BD-SCZ comparisons. Our findings suggest that metabolic characteristics in plasma vary across psychiatric disorders and that critical metabolites provide new clues regarding molecular mechanisms in these three psychiatric disorders.

Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations.

Aberrant tumor metabolism is a hallmark of cancer in which metabolic rewiring can support tumor growth under nutrient deficient conditions. KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are difficult to treat. The relationship between mutant KRAS and aberrant metabolism in CRCs has not been fully explored and could be a target for intervention. We previously acquired non-targeted metabolomics data from 161 tumor tissues and 39 normal colon tissues from stage I-III chemotherapy naïve CRC patients. In this study, we revealed that only in male patients, tumors with KRAS mutations had several altered pathways that suppress ferroptosis, including glutathione biosynthesis, transsulfuration activity, and methionine metabolism. To validate this phenotype, MC38 CRC cells (KRASG13R) were treated with a ferroptosis inducer; RAS-selected lethal (RSL3). RSL3 altered metabolic pathways in the opposite direction to that seen in KRAS mutant tumors from male patients confirming a suppressed ferroptosis metabolic phenotype in these patients. We further validated gene expression data from an additional CRC patient cohort (Gene Expression Omnibus (GEO)), and similarly observed differences in ferroptosis-related genes by sex and KRAS status. Further examination of the relationship between these genes and overall survival (OS) in the GEO cohort showed that KRAS mutant tumors are associated with poorer 5-year OS compared to KRAS wild type tumors, and only in male patients. Additionally, high compared to low expression of GPX4, FTH1, FTL, which suppress ferroptosis, were associated with poorer 5-year OS only in KRAS mutant tumors from male CRC patients. Additionally, low compared to high expression of ACSL4 was associated with poorer OS for this group. Our results show that KRAS mutant tumors from male CRC patients have suppressed ferroptosis, and gene expression changes that suppress ferroptosis associate with adverse outcomes for these patients, revealing a novel potential avenue for therapeutic approaches.

Discovery of decreased ferroptosis in male colorectal cancer patients with KRAS mutations.

Aberrant tumor metabolism is a hallmark of cancer in which metabolic rewiring can support tumor growth under nutrient deficient conditions. KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are difficult to treat. The relationship between mutant KRAS and aberrant metabolism in CRCs has not been fully explored and could be a target for intervention. We previously acquired non-targeted metabolomics data from 161 tumor tissues and 39 normal colon tissues from stage I-III chemotherapy naïve CRC patients. In this study, we revealed that tumors from male patients with KRAS mutations only, had several altered pathways that suppress ferroptosis, including glutathione biosynthesis, transsulfuration activity, and methionine metabolism. To validate this phenotype, MC38 CRC cells (KRAS G13R ) were treated with a ferroptosis inducer; RAS-selected lethal (RSL3). RSL3 altered metabolic pathways in the opposite direction to that seen in KRAS mutant tumors from male patients confirming a suppressed ferroptosis metabolic phenotype in these patients. We further validated gene expression data from an additional CRC patient cohort (Gene Expression Omnibus (GEO), and similarly observed differences in ferroptosis-related genes by sex and KRAS status. Further examination of the relationship between these genes and overall survival (OS) in the GEO cohort showed that KRAS mutant tumors are associated with poorer 5-year OS compared to KRAS wild type tumors, and only in male patients. Additionally, high compared to low expression of GPX4, FTH1, FTL , which suppressed ferroptosis, were associated with poorer 5-year OS only in KRAS mutant tumors from male CRC patients. Low compared to high expression of ACSL4 was associated with poorer OS for this group. Our results show that KRAS mutant tumors from male CRC patients have suppressed ferroptosis, and gene expression changes that suppress ferroptosis associate with adverse outcomes for these patients, revealing a novel potential avenue for therapeutic approaches.

Serum metabolic traits reveal therapeutic toxicities and responses of neoadjuvant chemoradiotherapy in patients with rectal cancer.

Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for patients with locally advanced rectal cancer (LARC). Therapeutic efficacy of nCRT is significantly affected by treatment-induced diarrhea and hematologic toxicities. Metabolic alternations in cancer therapy are key determinants to therapeutic toxicities and responses, but exploration in large-scale clinical studies remains limited. Here, we analyze 743 serum samples from 165 LARC patients recruited in a phase III clinical study using untargeted metabolomics and identify responsive metabolic traits over the course of nCRT. Pre-therapeutic serum metabolites successfully predict the chances of diarrhea and hematologic toxicities during nCRT. Particularly, levels of acyl carnitines are linked to sex disparity in nCRT-induced diarrhea. Finally, we show that differences in phenylalanine metabolism and essential amino acid metabolism may underlie distinct therapeutic responses of nCRT. This study illustrates the metabolic dynamics over the course of nCRT and provides potential to guide personalized nCRT treatment using responsive metabolic traits.

Bile acid distributions, sex-specificity, and prognosis in colorectal cancer.

BACKGROUND: Bile acids are known to be genotoxic and contribute to colorectal cancer (CRC). However, the link between CRC tumor bile acids to tumor location, patient sex, microbiome, immune-regulatory cells, and prognosis is not clear. METHODS: We conducted bile acid analysis using targeted liquid chromatography-mass spectrometry (LC-MS) on tumor tissues from CRC patients (n = 228) with survival analysis. We performed quantitative immunofluorescence (QIF) on tumors to examine immune cells. RESULTS: Twelve of the bile acids were significantly higher in right-sided colon tumors compared to left-sided colon tumors. Furthermore, in male patients, right-sided colon tumors had elevated secondary bile acids (deoxycholic acid, lithocholic acid, ursodeoxycholic acid) compared to left-sided colon tumors, but this difference between tumors by location was not observed in females. A high ratio of glycoursodeoxycholic to ursodeoxycholic was associated with 5-year overall survival (HR = 3.76, 95% CI = 1.17 to 12.1, P = 0.026), and a high ratio of glycochenodeoxycholic acid to chenodeoxycholic acid was associated with 5-year recurrence-free survival (HR = 3.61, 95% CI = 1.10 to 11.84, P = 0.034). We also show correlation between these bile acids and FoxP3 + T regulatory cells. CONCLUSIONS: This study revealed that the distribution of bile acid abundances in colon cancer patients is tumor location-, age- and sex-specific, and are linked to patient prognosis. This study provides new implications for targeting bile acid metabolism, microbiome, and immune responses for colon cancer patients by taking into account primary tumor location and sex.

Impact of preoperative carbohydrate loading on gastric volume in patients with type 2 diabetes.

BACKGROUND: Enhanced recovery after surgery advocates that consuming carbohydrates two hours before anesthesia is beneficial to the patient's recovery. Patients with diabetes are prone to delayed gastric emptying. Different guidelines for preoperative carbohydrate consumption in patients with diabetes remain controversial due to concerns about the risk of regurgitation, aspiration and hyperglycemia. Ultrasonic gastric volume (GV) assessment and blood glucose monitoring can comprehensively evaluate the safety and feasibility of preoperative carbohydrate intake in type 2 diabetes (T2D) patients. AIM: To evaluate the impact of preoperative carbohydrate loading on GV before anesthesia induction in T2D patients. METHODS: Patients with T2D receiving surgery under general anesthesia from December 2019 to December 2020 were included. A total of 78 patients were randomly allocated to 4 groups receiving 0, 100, 200, or 300 mL of carbohydrate loading 2 h before anesthesia induction. Gastric volume per unit weight (GV/W), Perlas grade, changes in blood glucose level, and risk of reflux and aspiration were evaluated before anesthesia induction. RESULTS: No significant difference was found in GV/W among the groups before anesthesia induction (P > 0.05). The number of patients with Perlas grade II and GV/W > 1.5 mL/kg did not differ among the groups (P > 0.05). Blood glucose level increased by > 2 mmol/L in patients receiving 300 mL carbohydrate drink, which was significantly higher than that in groups 1 and 2 (P < 0.05). CONCLUSION: Preoperative carbohydrate loading < 300 mL 2 h before induction of anesthesia in patients with T2D did not affect GV or increase the risk of reflux and aspiration. Blood glucose levels did not change significantly with preoperative carbohydrate loading of < 200 mL. However, 300 mL carbohydrate loading may increase blood glucose levels in patients with T2D before induction of anesthesia.

Analgesia and stress attenuation of ultrasound-guided modified pectoral nerve block type-II with different volumes of 0.3% ropivacaine in patients undergoing modified radical mastectomy for breast cancer: A prospective parallel randomized double-blind controlled clinical trial.

WHAT IS KNOWN AND OBJECTIVE: A previous randomized clinical trial concluded that an optimal concentration of 0.3% ropivacaine could provide satisfactory analgesia for breast cancer patients undergoing modified radical mastectomy. We wondered if a smaller volume (30 ml vs. 40 ml) of 0.3% ropivacaine could still provide adequate analgesia in an ultrasound-guided PECS II block in modified radical mastectomy. METHODS: We performed a prospective parallel randomized double-blind controlled clinical trial. Eligible patients were assigned to either the P30 or P40 group (30 or 40 ml of 0.3% ropivacaine, respectively). The skin area of hypoesthesia, anaesthetic plane determined with ultrasound, pain visual analogue scale (VAS), anaesthetic dosages, and complications were recorded. Serum levels of interleukin-1ß and interleukin-6 were measured postoperatively. RESULTS AND DISCUSSION: A total of 40 patients completed the trials, with 20 patients in each group. Although the skin area of hypoesthesia and the anaesthetic planes were significantly larger in the P40 group compared with the P30 group (p < 0.05), the VAS, analgesic and opioid doses, serum cytokine levels, anaesthetic toxicity, and complications had no significant differences between the two groups. WHAT IS NEW AND CONCLUSION: Compared with 40 ml, 30 ml of 0.3% ropivacaine could provide adequate analgesia and reduce surgical stress in patients undergoing modified radical mastectomy for breast cancer.

Asparagine Metabolism in Tumors Is Linked to Poor Survival in Females with Colorectal Cancer: A Cohort Study.

The interplay between the sex-specific differences in tumor metabolome and colorectal cancer (CRC) prognosis has never been studied and represents an opportunity to improve patient outcomes. This study examines the link between tumor metabolome and prognosis by sex for CRC patients. Using untargeted metabolomics analysis, abundances of 91 metabolites were obtained from primary tumor tissues from 197 patients (N = 95 females, N = 102 males) after surgical colectomy for stage I-III CRC. Cox Proportional hazard (PH) regression models estimated the associations between tumor metabolome and 5-year overall survival (OS) and recurrence-free survival (RFS), and their interactions with sex. Eleven metabolites had significant sex differences in their associations with 5-year OS, and five metabolites for 5-year RFS. The metabolites asparagine and serine had sex interactions for both OS and RFS. Furthermore, in the asparagine synthetase (ASNS)-catalyzed asparagine synthesis pathway, asparagine was associated with substantially poorer OS (HR (95% CI): 6.39 (1.78-22.91)) and RFS (HR (95% CI): 4.36 (1.39-13.68)) for female patients only. Similar prognostic disadvantages in females were seen in lysophospholipid and polyamine synthesis. Unique metabolite profiles indicated that increased asparagine synthesis was associated with poorer prognosis for females only, providing insight into precision medicine for CRC treatment stratified by sex.

YIV-906 potentiated anti-PD1 action against hepatocellular carcinoma by enhancing adaptive and innate immunity in the tumor microenvironment.

YIV-906 (PHY906) is a standardized botanical cancer drug candidate developed with a systems biology approach-inspired by a traditional Chinese herbal formulation, historically used to treat gastrointestinal symptoms including diarrhea, nausea and vomiting. In combination with chemotherapy and/or radiation therapy, preclinical and clinical results suggest that YIV-906 has the potential to prolong survival and improve quality of life for cancer patients. Here, we demonstrated that YIV-906 plus anti-PD1 could eradicate all Hepa 1-6 tumors in all tumor bearing mice. YIV-906 was found to have multiple mechanisms of action to enhance adaptive and innate immunity. In combination, YIV-906 reduced PD1 or counteracted PD-L1 induction caused by anti-PD1 which led to higher T-cell activation gene expression of the tumor. In addition, YIV-906 could reduce immune tolerance by modulating IDO activity and reducing monocytic MDSC of the tumor. The combination of anti-PD1 and YIV-906 generated acute inflammation in the tumor microenvironment with more M1-like macrophages. YIV-906 could potentiate the action of interferon gamma (IFNg) to increase M1-like macrophage polarization while inhibiting IL4 action to decrease M2 macrophage polarization. Flavonoids from YIV-906 were responsible for modulating IDO activity and potentiating IFNg action in M1-like macrophage polarization. In conclusion, YIV-906 could act as an immunomodulator and enhance the innate and adaptive immune response and potentiate anti-tumor activity for immunotherapies to treat cancer.

Identification of Dose-Dependent DNA Damage and Repair Responses From Subchronic Exposure to 1,4-Dioxane in Mice Using a Systems Analysis Approach.

1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States. Although it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, female BDF-1 mice were exposed to 1,4-DX (0, 50, 500, and 5,000mg/L) in their drinking water for 1 or 4 weeks, to explore the toxic effects. Histopathological studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Immunohistochemical analysis of the liver revealed increased H2AXγ-positive hepatocytes (a marker of DNA double-strand breaks), and an expansion of precholangiocytes (reflecting both DNA damage and repair mechanisms) after exposure. Liver transcriptomics revealed 1,4-DX-induced perturbations in signaling pathways predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, feces, and urine metabolomic profiling revealed no effect of 1,4-DX exposure, and bile acid quantification in liver and feces similarly showed no effect of exposure. We speculate that the results may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death but have activated the repair systems in response to 1,4-DX exposure.

Tumor Tissue-Specific Biomarkers of Colorectal Cancer by Anatomic Location and Stage.

The progress in the discovery and validation of metabolite biomarkers for the detection of colorectal cancer (CRC) has been hampered by the lack of reproducibility between study cohorts. The majority of discovery-phase biomarker studies have used patient blood samples to identify disease-related metabolites, but this pre-validation phase is confounded by non-specific disease influences on the metabolome. We therefore propose that metabolite biomarker discovery would have greater success and higher reproducibility for CRC if the discovery phase was conducted in tumor tissues, to find metabolites that have higher specificity to the metabolic consequences of the disease, that are then validated in blood samples. This would thereby eliminate any non-tumor and/or body response effects to the disease. In this study, we performed comprehensive untargeted metabolomics analyses on normal (adjacent) colon and tumor tissues from CRC patients, revealing tumor tissue-specific biomarkers (n = 39/group). We identified 28 highly discriminatory tumor tissue metabolite biomarkers of CRC by orthogonal partial least-squares discriminant analysis (OPLS-DA) and univariate analyses (VIP > 1.5, p < 0.05). A stepwise selection procedure was used to identify nine metabolites that were the most predictive of CRC with areas under the curve (AUCs) of >0.96, using various models. We further identified five biomarkers that were specific to the anatomic location of tumors in the colon (n = 236). The combination of these five metabolites (S-adenosyl-L-homocysteine, formylmethionine, fucose 1-phosphate, lactate, and phenylalanine) demonstrated high differentiative capability for left- and right-sided colon cancers at stage I by internal cross-validation (AUC = 0.804, 95% confidence interval, CI 0.670-0.940). This study thus revealed nine discriminatory biomarkers of CRC that are now poised for external validation in a future independent cohort of samples. We also discovered a discrete metabolic signature to determine the anatomic location of the tumor at the earliest stage, thus potentially providing clinicians a means to identify individuals that could be triaged for additional screening regimens.

Sex Differences in Colon Cancer Metabolism Reveal A Novel Subphenotype.

Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes among all CRC patients. Aberrant metabolism is a known hallmark and therapeutic target for cancer. We propose that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation, and differences in environmental milieu of the colon which vary between the sexes. Metabolomics analysis of patient colon tumors (n = 197) and normal tissues (n = 39) revealed sex-specific metabolic subphenotypes dependent on anatomic location. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production to fuel asparagine synthesis and amino acid uptake. The clinical importance of our findings were further investigated in an independent data set from The Cancer Genomic Atlas, and demonstrated that high asparagine synthetase (ASNS) expression correlated with poorer survival for women. This is the first study to show a unique, nutrient-deplete metabolic subphenotype in women with RCC, with implications for tumor progression and outcomes in CRC patients.

Gene Alterations of N6-Methyladenosine (m6A) Regulators in Colorectal Cancer: A TCGA Database Study.

N6-methyladenosine (m6A) plays an important role in many cancers. However, few studies have examined the role of m6A in colorectal CRC. To examine the effect of m6A on CRC, we studied the genome of 591 CRC cases from The Cancer Genome Atlas (TCGA). The relationship between the messenger RNA (mRNA) expression, copy number variation (CNVs), and mutations of m6A "Writers," "Readers," and "Erasers," prognosis, immune cell infiltration, and genetic mutations in CRC cases were analyzed. CNVs and mutations were found in thirteen m6A regulators. As expected, gain and amplification of m6A regulators increased the mRNA expression of these regulators, while deletion led to reduction in the mRNA expression. Moreover, CNVs and mutation of these regulators were significantly associated with APC, TP53, and microsatellite instability (MSI) status (p < 0.001, p < 0.001, and p = 0.029, respectively). CNVs of m6A regulators also correlated with inferred immune cell infiltration in CRC tissues, especially in colon tissues. Additionally, alterations of RBM15, YTHDF2, YTHDC1, YTHDC2, and METTL14 genes were related to the worse overall survival and disease-free survival (DFS) of CRC patients. Specifically, the deletion status of "Writers" was also correlated to the DFS of CRC patients (p = 0.02). Gene set enrichment analysis found that FTO was involved in mRNA 3' end processing, polyubiquitin binding, and RNA polymerase promoter elongation, while YTHDC1 was related to interferon-alpha and gamma response. In conclusion, a novel relationship was identified between CNVs and mutations of m6A regulators with prognosis and inferred immune function of CRC. These findings will improve the understanding of the relationship of m6A in CRC.

Molecular Pathway Analysis Indicates a Distinct Metabolic Phenotype in Women With Right-Sided Colon Cancer.

Colon cancer is the third most commonly diagnosed cancer in the United States. Recent reports have shown that the location of the primary tumor is of clinical importance. Patients with right-sided colon cancers (RCCs) (tumors arising between the cecum and proximal transverse colon) have poorer clinical outcomes than those with left-sided colon cancers (LCCs) (tumors arising between the distal transverse colon and sigmoid colon, excluding the rectum). Interestingly, women have a lower incidence of colon cancer than men, but have a higher propensity for RCC. The reason for this difference is not known; however, identification of sex-specific differences in gene expression by tumor anatomical location in the colon could provide further insight. Moreover, it could reveal important predictive markers for response to various treatments. This study provides a comprehensive bioinformatic analysis of various genes and molecular pathways that correlated with sex and anatomical location of colon cancers using four publicly available annotated data sets housed in the National Center for Biotechnology Information's Gene Expression Omnibus. We identified differentially expressed genes in tumor tissues from women with RCC, which showed attenuated energy and nutrient metabolism when compared with women with LCC. Specifically, we showed the downregulation of 5' AMP-activated protein kinase alpha subunit (AMPKα) and anti-tumor immune responses in women with RCC. This difference was not seen when comparing tumor tissues from men with RCC to men with LCC. Therefore, women with RCC may have a specific metabolic and immune phenotype which accounts for differences in prognosis and treatment response.

Clinical significance of soluble adhesion molecules in anti-NMDAR encephalitis patients.

Increasing evidence indicates that immune system dysfunction affects anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. This study aims to investigate the relationship between adhesion molecules and the pathophysiology in anti-NMDAR encephalitis. Soluble forms of Intercellular adhesion molecule-1 (sICAM-1), vascular adhesion molecule-1 (sVCAM-1), and L-selectin (sL-selectin), were measured in the CSF and serum of 26 participants with anti-NMDAR encephalitis, 11 patients with schizophrenia and 22 patients with noninflammatory disorders. CSF levels of sICAM-1, sVCAM-1 and sL-selectin were significantly elevated in the anti-NMDAR encephalitis group. sVCAM-1 levels were positively associated with modified Rankin scale score in anti-NMDAR encephalitis patients at the onset and 3-month follow-up.

Palbociclib and Fulvestrant Act in Synergy to Modulate Central Carbon Metabolism in Breast Cancer Cells.

The aims of this study were to determine whether combination chemotherapeutics exhibit a synergistic effect on breast cancer cell metabolism. Palbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6, and when patients are treated in combination with fulvestrant, an estrogen receptor antagonist, they have improved progression-free survival. The mechanisms for this survival advantage are not known. Therefore, we analyzed metabolic and transcriptomic changes in MCF-7 cells following single and combination chemotherapy to determine whether selective metabolic pathways are targeted during these different modes of treatment. Individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy's synergism in the cell model. This study also highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.

SWATHtoMRM: Development of High-Coverage Targeted Metabolomics Method Using SWATH Technology for Biomarker Discovery.

The complexity of metabolome presents a great analytical challenge for quantitative metabolite profiling, and restricts the application of metabolomics in biomarker discovery. Targeted metabolomics using multiple-reaction monitoring (MRM) technique has excellent capability for quantitative analysis, but suffers from the limited metabolite coverage. To address this challenge, we developed a new strategy, namely, SWATHtoMRM, which utilizes the broad coverage of SWATH-MS technology to develop high-coverage targeted metabolomics method. Specifically, SWATH-MS technique was first utilized to untargeted profile one pooled biological sample and to acquire the MS2 spectra for all metabolites. Then, SWATHtoMRM was used to extract the large-scale MRM transitions for targeted analysis with coverage as high as 1000-2000 metabolites. Then, we demonstrated the advantages of SWATHtoMRM method in quantitative analysis such as coverage, reproducibility, sensitivity, and dynamic range. Finally, we applied our SWATHtoMRM approach to discover potential metabolite biomarkers for colorectal cancer (CRC) diagnosis. A high-coverage targeted metabolomics method with 1303 metabolites in one injection was developed to profile colorectal cancer tissues from CRC patients. A total of 20 potential metabolite biomarkers were discovered and validated for CRC diagnosis. In plasma samples from CRC patients, 17 out of 20 potential biomarkers were further validated to be associated with tumor resection, which may have a great potential in assessing the prognosis of CRC patients after tumor resection. Together, the SWATHtoMRM strategy provides a new way to develop high-coverage targeted metabolomics method, and facilitates the application of targeted metabolomics in disease biomarker discovery. The SWATHtoMRM program is freely available on the Internet ( http://www.zhulab.cn/software.php ).

Alcohol Consumption Is a Risk Factor for Lower Extremity Arterial Disease in Chinese Patients with T2DM.

OBJECTIVE: To investigate the relationship between alcohol consumption and diabetic lower extremity arterial disease (LEAD) in hospitalized patients with type 2 diabetes mellitus (T2DM). METHODS: We evaluated 138 hospitalized patients with T2DM who consumed alcohol and 833 who did not. We used propensity score matching to reduce the confounding bias between groups. Additionally, a logistic regression analysis was performed with the matched data to evaluate the LEAD risk. RESULTS: In total, 119 pairs of patients who did and did not consume alcohol were matched. According to the logistic regression analysis, patients who consumed >8 U of alcohol/day had a higher risk of LEAD (odds ratio (OR): 6.35, 95% confidence interval (CI): 1.78-22.65) than patients who did not consume alcohol. Additionally, after adjusting for age, gender, region, occupation, smoking status, body mass index, weight change, and duration of diabetes, the OR of peripheral artery disease after >20 years of alcohol consumption was 3.48 (95% CI: 1.09-11.15). Furthermore, we observed a significant dose-response relationship between alcohol consumption and LEAD. CONCLUSIONS: Alcohol consumption may be a risk factor of LEAD in patients with T2DM. Patients with T2DM should be advised to stop drinking, to prevent the onset of LEAD.