Machine Learning-Based Integrated Multiomics Characterization of Colorectal Cancer Reveals Distinctive Metabolic Signatures.

The metabolic signature identification of colorectal cancer is critical for its early diagnosis and therapeutic approaches that will significantly block cancer progression and improve patient survival. Here, we combined an untargeted metabolic analysis strategy based on internal extractive electrospray ionization mass spectrometry and the machine learning approach to analyze metabolites in 173 pairs of cancer samples and matched normal tissue samples to build robust metabolic signature models for diagnostic purposes. Screening and independent validation of metabolic signatures from colorectal cancers via machine learning methods (Logistic Regression_L1 for feature selection and eXtreme Gradient Boosting for classification) was performed to generate a panel of seven signatures with good diagnostic performance (the accuracy of 87.74%, sensitivity of 85.82%, and specificity of 89.66%). Moreover, seven signatures were evaluated according to their ability to distinguish between cancer and normal tissues, with the metabolic molecule PC (30:0) showing good diagnostic performance. In addition, genes associated with PC (30:0) were identified by multiomics analysis (combining metabolic data with transcriptomic data analysis) and our results showed that PC (30:0) could promote the proliferation of colorectal cancer cell SW480, revealing the correlation between genetic changes and metabolic dysregulation in cancer. Overall, our results reveal potential determinants affecting metabolite dysregulation, paving the way for a mechanistic understanding of altered tissue metabolites in colorectal cancer and design interventions for manipulating the levels of circulating metabolites.

Global burden and prediction study of cutaneous squamous cell carcinoma from 1990 to 2030: A systematic analysis and comparison with China.

Background: China has the highest number of new cancer cases and deaths globally. Due to particularly low scores in health care quality for cutaneous squamous cell carcinoma (cSCC), the country's cSCC burden requires greater awareness. Consequently, we aimed to evaluate and predict the trend of the cSCC burden globally and in China from 1990 to 2030. Methods: We retrieved data from the Global Burden of Disease 2019 study, which provided estimates of the incidence, mortality, prevalence, and disability-adjusted life years (DALYs) of cSCC from 1990 to 2019. We set up joint-point analyses and Bayesian age-period-cohort (BAPC) models to predict the disease burden of cSCC up to 2030. Results: In 2019, China reported age-standardised rates of cSCC prevalence, incidence, mortality, and DALYs of 2.54, 2.12, 0.88, and 16.76 per 100 000 population, respectively. The country's prevalence and incidence rates from 1990 to 2019 were lower than the global levels, but its mortality and DALY rates were higher. The age-standardised rates were higher for males, and the disease burden increased with each age group globally and in China. Moreover, the average annual percentage change showed all indicators were growing faster than the global levels. According to the BAPC model, there will be an upward trend in the prevalence and incidence globally and in China between 2020 and 2030, with a decrease in mortality and DALYs. Conclusions: We observed an upward trend in the cSCC burden over the past 30 years in China. Prevalence and incidence are expected to continue at a higher rate than the global average in the next decade, while mortality and DALYs are predicted to decrease. As the Chinese population ages, efforts toward managing and preventing cSCC should be targeted towards the elderly population.

Targeted metabolomic profiles of serum amino acids are independently correlated with malnutrition in older adults.

BACKGROUND: Malnutrition is a common geriatric syndrome that is closely associated with adverse clinical outcomes and poses significant harm to older adults. Early assessment of nutritional status plays a crucial role in preventing and intervening in cases of malnutrition. However, there is currently a lack of measurable methods and biomarkers to evaluate malnutrition in older adults accurately. The aim of this study is to investigate the independent correlation between serum levels of amino acids and malnutrition in older adults, and to identify effective metabolomics biomarkers that can aid in the early detection of geriatric malnutrition. METHODS: A total of 254 geriatric medical examination participants from Beijing Hospital were included in the study, consisting of 182 individuals with normal nutritional status (Normal group) and 72 patients at risk of malnutrition or already malnourished (MN group). Malnutrition was assessed using the Mini-Nutritional Assessment Short-Form (MNA-SF). Demographic data were collected, and muscle-related and lipid indexes were determined. Serum amino acid concentrations were measured using isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS). The correlation between serum amino acid levels and malnutrition was analyzed using non-parametric tests, partial correlation analysis, linear regression, and logistic regression. RESULTS: The geriatric MN group exhibited significantly lower serum aromatic amino acid levels (P < 0.05) compared to the normal group. A positive correlation was observed between serum aromatic amino acid levels and the MNA-SF score (P = 0.002), as well as with known biomarkers of malnutrition such as body mass index (BMI) (P < 0.001) and hemoglobin (HGB) (P = 0.005). Multivariable logistic or linear regression analyses showed that aromatic amino acid levels were negatively correlated with MN and positively correlated with the MNA-SF score, after adjusting for some confounding factors, such as age, gender, BMI, smoking status, history of dyslipidemia, diabetes mellitus and frailty. Stratified analyses revealed that these trends were more pronounced in individuals without a history of frailty compared to those with a history of frailty, and there was an interaction between aromatic amino acid levels and frailty history (P = 0.004). CONCLUSION: Our study suggests that serum aromatic amino acids are independently associated with malnutrition in older adults. These results have important implications for identifying potential biomarkers to predict geriatric malnutrition or monitor its progression and severity, as malnutrition can result in poor clinical outcomes.

Quantifying carboxymethyl lysine and carboxyethyl lysine in human plasma: clinical insights into aging research using liquid chromatography-tandem mass spectrometry.

OBJECTIVE: The objective of this study was to establish a methodology for determining carboxymethyl lysine (CML) and carboxyethyl lysine (CEL) concentrations in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The test results were also used for clinical aging research. METHODS: Human plasma samples were incubated with aqueous perfluorovaleric acid (NFPA), succeeded by precipitation utilizing trichloroacetic acid, hydrolysis facilitated by hydrochloric acid, nitrogen drying, and ultimate re-dissolution utilizing NFPA, followed by filtration. Cotinine-D3 was added as an internal standard. The separation was performed on an Agela Venusil ASB C18 column (50 mm × 4.6 mm, 5 µm) with a 5 mmol/L NFPA and acetonitrile/water of 60:40 (v/v) containing 0.15% formic acid. The multiple reaction monitoring mode was used for detecting CML, CEL, and cotinine-D3, with ion pairs m/z 205.2 > 84.1 (for quantitative) and m/z 205.2 > m/z 130.0 for CML, m/z 219.1 > 84.1 (for quantitative) and m/z 219.1 > m/z 130.1 for CEL, and m/z 180.1 > 80.1 for cotinine-D3, respectively. RESULTS: The separation of CML and CEL was accomplished within a total analysis time of 6 minutes. The retention times of CML, CEL, and cotinine-D3 were 3.43 minutes, 3.46 minutes, and 4.50 minutes, respectively. The assay exhibited linearity in the concentration range of 0.025-1.500 µmol/L, with a lower limit of quantification of 0.025 µmol/L for both compounds. The relative standard deviations of intra-day and inter-day were both below 9%, and the relative errors were both within the range of ±4%. The average recoveries were 94.24% for CML and 97.89% for CEL. CONCLUSION: The results indicate that the developed methodology is fast, highly sensitive, highly specific, reproducible, and suitable for the rapid detection of CML and CEL in clinical human plasma samples. The outcomes of the clinical research project on aging underscored the important indicative significance of these two indicators for research on human aging.

Utilizing serum metabolomics for assessing postoperative efficacy and monitoring recurrence in gastric cancer patients.

OBJECTIVE: (1) This study aims to identify distinct serum metabolites in gastric cancer patients compared to healthy individuals, providing valuable insights into postoperative efficacy evaluation and monitoring of gastric cancer recurrence; (2) Methods: Serum samples were collected from 15 healthy individuals, 16 gastric cancer patients before surgery, 3 months after surgery, 6 months after surgery, and 15 gastric cancer recurrence patients. T-test and analysis of variance (ANOVA) were performed to screen 489 differential metabolites between the preoperative group and the healthy control group. Based on the level of the above metabolites in the recurrence, preoperative, three-month postoperative, and six-month postoperative groups, we further selected 18 significant differential metabolites by ANOVA and partial least squares discriminant analysis (PLS-DA). The result of hierarchical clustering analysis about the above metabolites showed that the samples were regrouped into the tumor-bearing group (comprising the original recurrence and preoperative groups) and the tumor-free group (comprising the original three-month postoperative and six-month postoperative groups). Based on the results of PLS-DA, 7 differential metabolites (VIP > 1.0) were further selected to distinguish the tumor-bearing group and the tumor-free group. Finally, the results of hierarchical clustering analysis showed that these 7 metabolites could well identify gastric cancer recurrence; (3) Results: Lysophosphatidic acids, triglycerides, lysine, and sphingosine-1-phosphate were significantly elevated in the three-month postoperative, six-month postoperative, and healthy control groups, compared to the preoperative and recurrence groups. Conversely, phosphatidylcholine, oxidized ceramide, and phosphatidylglycerol were significantly reduced in the three-month postoperative, six-month postoperative, and healthy control groups compared to the preoperative and recurrence groups. However, these substances did not show significant differences between the preoperative and recurrence groups, nor between the three-month postoperative, six-month postoperative, and healthy control groups; (4) Conclusions: Our findings demonstrate the presence of distinct metabolites in the serum of gastric cancer patients compared to healthy individuals. Lysophosphatidic acid, triglycerides, lysine, sphingosine-1-phosphate, phosphatidylcholine, oxidized ceramide, and phosphatidylglycerol hold potential as biomarkers for evaluating postoperative efficacy and monitoring recurrence in gastric cancer patients. These metabolites exhibit varying concentrations across different sample categories.

Multifunctional biocompatible Ni/Ni-P nanospheres for anti-tumor "neoadjuvant phototherapy" combining photothermal therapy and photodynamic therapy.

Gastric cancer, a gastrointestinal tumor with high morbidity and lethality, is often treated using strategies that are not as effective as they could be due to the locally advanced stage. Although pre-operative neoadjuvant chemotherapy can degrade the tumor stage to afford the possibility of surgery, it still possesses the problems of high systemic toxicity and low selectivity. In this work, we constructed an intelligent multi-functional nanoplatform (NNPIP NPs) with synergistic effects of photothermal therapy (PTT) and photodynamic therapy (PDT), which consisted of the nickel/nickel phosphide (Ni/Ni-P) nanosphere as the core, polyethyleneimine (PEI) as the shell, and the loaded indocyanine green (ICG). The mutual reinforcement of heat generated by the core and photosensitizer under 808 nm NIR laser irradiation is highly effective in the synergistic action of PTT. And co-delivery of ICG with nanoparticles into the cell enhances the PDT effect by reducing the consumption of singlet oxygen (1O2). Ultimately, this therapeutic strategy in vivo not only shrunk tumors but even eliminated tumors completely in a quarter of samples, which may be considered as a potential alternative to neoadjuvant chemotherapy and called "neoadjuvant phototherapy". In addition, as a nanoplatform based on transition metal nickel, NNPIP NPs could also be considered as a potential contrast agent for T1-weighted magnetic resonance imaging (MRI). Herein, we can diagnose and achieve pre-surgical downstaging of tumors and hope to improve R0 resection rates with lower toxicity and higher selectivity.

Comparative efficacy of different reconstruction methods after wide local excision of the nail unit: A retrospective study.

BACKGROUND: Wide local excision (WLE) of the nail unit is widely used in treating in situ and minimally invasive malignant subungual tumours. After WLE, diverse reconstruction methods have been reported. However, the best repair method has yet to be determined. OBJECTIVE: To compare the repair effects and postoperative morbidity of secondary intention healing (SIH), artificial dermis grafting combined with secondary intention healing (ADGSIH) and full-thickness skin grafting (FSG) after WLE of the nail unit. METHODS: We retrospectively reviewed 21 patients who underwent WLE of the nail unit. The re-epithelializing time, functional and cosmetic outcomes, postoperative complications and patients' satisfaction were assessed from the follow-up records. RESULTS: The FSG group showed more rapid healing and better functional and cosmetic outcomes than the SIH and ADGSIH groups. The ADGSIH and FSG groups showed significant pain relief compared to the SIH group. No serious early and late postoperative complications were reported. The median follow-up period was 26 months, and no recurrence was observed. All patients were satisfied with the treatment. CONCLUSIONS: FSG after the WLE of the nail unit is a therapeutic option with convenient application, significant pain relief, rapid recovery and satisfying functional and cosmetic outcomes.

The efficacy of dermoscopy in defining the surgical margins of cutaneous squamous cell carcinoma: a retrospective study.

Objective: To investigate the diagnostic value of dermoscopy in defining the tumor margin of cutaneous squamous cell carcinoma (cSCC) for the appropriate surgical margin. Methods: A total of 90 cSCC patients were enrolled in the study. All patients were recruited into two groups: those who preserved intact macroscopic features of neoplasms without or after incisional biopsy and those with uncertain residual tumors after excisional biopsy. A dermoscopy-defined surgical margin of 8mm outward was used according to the tumor boundaries observed with the naked eye and dermoscopy. All excised tumor specimens were divided into serial sections according to the four "3, 6, 9, 12" directions at every 4-mm interval from the dermoscopy-detected tumor margin. Pathological examination was performed at 0 mm, 4 mm, and 8 mm margins to confirm tumor remnants. Results: Retrospective analysis of dermatoscopic results showed inconsistent clinical and dermatoscopic borders in 43 of 90 cases (47.8%). The ability of dermoscopy to detect tumor borders showed no statistical difference between the two groups (p > 0.05). In the unbiopsy or incisional biopsy group, 66.6% of the tumors were resected with a 4-mm margin and 98.3% with an 8-mm margin, with significant differences (p = 0.047). For patients with inconspicuous clinical evidence of residual tumor after excisional biopsy, the tumor clearance rate was 53.3% at 0 mm, 93.3% at 4 mm, and 100.0% at 8 mm. Statistically significant differences were noted between 0 mm and 4 mm (p = 0.017), as well as between 0 mm and 8 mm (p = 0.043) but did not differ between 4 mm and 8 mm (p > 0.05). Conclusions: Dermoscopy defined the tumor margin of cSCC better than visual inspection alone. Direct dermoscopic-guided surgery with at least 8-mm expansion was recommended for high-risk cSCC. Dermoscopy also assisted in identifying surgical margins at the healing biopsy site, making 8 mm still the recommended expansion range.

A new strategy for searching determinants in colorectal cancer progression through whole-part relationship combined with multi-omics.

The high incidence and mortality of colorectal cancer (CRC) and the lack of adequate diagnostic molecules have led to poor treatment outcomes for colorectal cancer, making it particularly important to develop methods to obtain molecular with significant diagnostic effects. Here, we proposed a whole and part study strategy (early-stage colorectal cancer as "part" and colorectal cancer as "whole") to identify specific and co-pathways of change in early-stage and colorectal cancers and to discover the determinants of colorectal cancer development. Metabolite biomarkers discovered in plasma may not necessarily reflect the pathological status of tumor tissue. To explore the determinant biomarkers associated with plasma and tumor tissue in the CRC progression, multi-omics were performed on three phases of biomarker discovery studies (discovery, identification and validation) including 128 plasma metabolomes and 84 tissue transcriptomes. Importantly, we observe that the metabolic levels of oleic acid and FA (18:2) in patients with colorectal cancer were much higher than in healthy people. Finally, biofunctional verification confirmed that oleic acid and FA (18:2) can promote the growth of colorectal cancer tumor cells and be used as plasma biomarkers for early-stage colorectal cancer. We propose a novel research strategy to discover co-pathways and important biomarkers that may be targeted for a potential role in early colorectal cancer, and our work provides a promising tool for the clinical diagnosis of colorectal cancer.

Colorectal cancer therapy mediated by nanomedicines.

Colorectal cancer is the third most malignant gastrointestinal tumor. Although traditional chemotherapy and radiotherapy have been widely used for treating colorectal cancer, the treatment effect is still unsatisfactory, resulting in a high mortality rate and a low 5-year survival rate. In recent years, with the development of molecular biology of colorectal cancer, many promising therapeutic strategies based on nanomaterials have been developed for colorectal cancer. In this review, we focus on recent advances in colorectal cancer treatment-related nanomedicines. We first discuss the exploration of stimuli-responsive drug delivery systems (DDSs) for colorectal cancer treatment using pH, hypoxia, glutathione (GSH), enzymes, light, magnetic fields (MF), and ultrasound (US) as stimuli. Moreover, the latest progress in emerging therapy for colorectal cancer is further summarized, including photothermal therapy (PTT), magnetothermal therapy (MTT), photodynamic therapy (PDT), sonodynamic therapy (SDT), and chemodynamic therapy (CDT). Finally, we explore the existing challenges and future directions for the better design and development of nanomedicines for clinical colorectal cancer treatment.

Association between gut microbiota and peptic ulcer disease, particularly gastric ulcer and duodenal ulcer: a two-sample Mendelian randomization study.

Background: Recent an observational study has suggested a potential connection between gut microbiota (GM) and peptic ulcer diseases (PUDs), particularly gastric ulcer (GU) and duodenal ulcer (DU). However, the causal connection remains unsure. Methods: A two-sample Mendelian randomization (MR) is carried out to explore the connection between the GM and DU or GU. Data on the GM comes from the MiBioGend database, and GU or DU data are based on the FinnGen database. One group of single nucleotide polymorphisms (SNPs) (P < 5 × 10-8) are served as instrumental variables (IVs). To obtain a more comprehensive conclusion, the other SNPs (P < 1 × 10-5) are selected as IVs. Inverse variance weighting (IVW) is used to determine the causal relationship. Results: At the level of P < 1 × 10-5, the IVW analysis suggests that Clostridiaceae1, Butyriccoccus, and Peptcoccus have harmful effects on GU, while LachnospiraceaeUCG004 and MollicutesRF9 have beneficial effects on GU. Then, in the case of DU, the IVW analysis suggested that Lentisphaeria, Negativicutes, Clostridiaceae1, ClostridiumseMnsustricto1, ErysipelotrichaceaeUCG003, LachnospiraceaeNC2004group, Selenomonadale, Victivallales, and Lentisphaerae have harmful effects, while Catenibacterium, Escherichia.Shigella, LachnospiraceaeUCG008, and Sutterella have beneficial effects. When P < 5 × 10-8, IVW analysis suggests that GM has no significant influence on GU or DU. Conclusion: This two-sample MR indicates a causal relationship between GM and GU or DU.

Expression patterns of hair-related keratins and epithelial keratins in onychopapilloma: The significance of clarifying the origin of onychopapilloma.

Background: Onychopapilloma is generally recognized as a benign tumor of the nail bed and distal matrix. However, the origin of onychopapilloma has not been explained yet. Objective: To clarify the origin of onychopapilloma, we detected the expression patterns of hair-related keratins and epithelial keratins, which are expressed specifically in the nail unit. Materials and methods: The clinical and histopathologic features of 11 patients with onychopapilloma were analyzed, and the expression patterns of hair-related and epithelial keratins were detected. Results: Histologically, all subjects showed acanthosis, papillomatosis and matrix metaplasia within the nail bed. Immunohistochemically, the expression pattern of keratins in our standard nail unit was consistent with previous reports. "Nail matrix-related keratins" HK31, HK34, HK85, and HK86 were only expressed in the nail matrix, and "Nail bed-related keratins" HK75 and K6/K16 were only expressed in the nail bed. However, in onychopapilloma, whether adjacent to the matrix or in the distal nail bed, all cases were positive for nail bed-related keratins and HK31 but negative for other nail matrix-related keratins. Conclusion: Our study suggests that onychopapilloma may originate from the nail bed rather than the nail matrix. Furthermore, the expression of nail bed-related keratins and HK31 could be used as diagnostic markers of onychopapilloma.

Association of levels of metabolites with the safe margin of rectal cancer surgery: a metabolomics study.

BACKGROUND: Rectal cancer is one of the most lethal of gastrointestinal malignancies. Metabonomics has gradually developed as a convenient, inexpensive and non-destructive technique for the study of cancers. METHODS: A total of 150 tissue samples from 25 rectal cancer patients were analyzed by liquid chromatography-mass spectrometry (LC-MS), and 6 tissue samples were collected from each patient (group 1: tumor; group 2: 0.5 cm from tumor; group 3:1 cm from tumor; group 4:2 cm from tumor; group 5:3 cm from tumor and group 6:5 cm from tumor). The differential metabolites of tumor tissues and 5 cm from the tumor (normal tissues) were first selected. The differential metabolites between tumor tissues and normal tissues were regrouped by hierarchical clustering analysis, and further selected by discriminant analysis according to the regrouping of clustering results. The potential safe margin of clinical T(cT)1,cT2 stage rectal cancer and cT3,cT4 stage rectal cancer at the metabolomic level was further identified by observing the changes in the level of differential metabolites within the samples from group 1 to group 6. RESULTS: We found 22 specific metabolites to distinguish tumor tissue and normal tissue. The most significant changes in metabolite levels were observed at 0.5 cm (cT1, cT2) and 2.0 cm (cT3, cT4) from the tumor, while the changes in the tissues afterwards showed a stable trend. CONCLUSIONS: There are differential metabolites between tumor tissues and normal tissues in rectal cancer. Based on our limited sample size, the safe distal incision margin for rectal cancer surgery in metabolites may be 0.5 cm in patients with cT1 and cT2 stage rectal cancer and 2.0 cm in patients with cT3 and cT4 stage rectal cancer.

Metabolic-Dysregulation-Based iEESI-MS Reveals Potential Biomarkers Associated with Early-Stage and Progressive Colorectal Cancer.

The application of rapid and accurate diagnostic methods can improve colorectal cancer (CRC) survival rates dramatically. Here, we used a non-targeted metabolic analysis strategy based on internal extractive electrospray ionization mass spectrometry (iEESI-MS) to detect metabolite ions associated with the progression of CRC from 172 tissues (45 stage I/II CRC, 41 stage III/IV CRC, and 86 well-matched normal tissues). A support vector machine (SVM) model based on 10 differential metabolite ions for differentiating early-stage CRC from normal tissues was built with a good prediction accuracy of 92.6%. The biomarker panel consisting of lysophosphatidylcholine (LPC) (18:0) has good diagnostic potential in differentiating early-stage CRC from advanced-stage CRC. We showed that the down-regulation of LPC (18:0) in tumor tissues is associated with CRC progression and related to the regulation of the epidermal growth factor receptor. Pathway analysis showed that metabolic pathways in CRC are related to glycerophospholipid metabolism and purine metabolism. In conclusion, we built an SVM model with good performance to distinguish between early-stage CRC and normal groups based on iEESI-MS and found that LPC (18:0) is associated with the progression of CRC.

The effect of dermoscopy in assisting on defining surgical margins of basal cell carcinoma.

To investigate the diagnostic value of dermoscopy in defining the tumor margin of basal cell carcinoma (BCC) for the appropriate surgical margin. A total of 107 BCC patients were enrolled for this study. The tumor boundaries were observed by naked eye and dermoscope respectively, and 5 mm outward was used as surgical margin according to the dermoscopy-defined margin. Pathological examinations were performed at 2 mm intervals in the direction previously marked and the effect was assessed accordingly. There were still 16.8% of patients whose visual margin was insufficient to the dermoscopy-detected margin. With 2 mm excision margin from the dermoscopy-guided tumor margin, excision range in 12 patients (11.2%) proved to be inadequate, but only 18 surgical margins (4.2%) in the whole 428 excision margin specimens proved to be tumor-positive. While with 4 mm margin, residual lesion was observed in 2 (0.5%) of 107 BCC patients, and positive margin was found in 2 (0.3%) of 428 margin specimen. There has been no recurrence in our study so far. Dermoscopy is superior to visual inspection for defining BCC tumor margin. Under preoperative dermoscopy detection, a 4 mm excision margin of BCC can achieve a radical resection rate of 98.1%, and 92.3% for a 2 mm excision margin of pigmented BCC.

Surgical repair for deformities of the nail unit.

The nail apparatus is the largest and most complex skin appendage. Defects in this unit can result in significant functional insufficiency and cosmetic disfigurement. Common nail deformities include split nail, short nail, onycholysis, nail malalignment, hooked nail, and absent nail. Currently, surgical repair is the primary treatment for such deformities. Based on the etiological and anatomical classifications, one or more appropriate operations can be selected to repair nail unit deformities. These include autologous fat grafting, longitudinal cicatrectomy, Z-plasties, nail bed elongation, split-thickness sterile matrix grafting, volar V-Y advanced flap reconstruction, sterile matrix particle grafting, germinal matrix flaps, and germinal matrix grafting. This review discusses the fundamental classification of nail unit deformities, common reconstructive surgical techniques, and their features.

Specific lysophosphatidylcholine and acylcarnitine related to sarcopenia and its components in older men.

BACKGROUND: Metabolic profiling may provide insights into the pathogenesis and identification of sarcopenia; however, data on the metabolic basis of sarcopenia and muscle-related parameters among older adults remain incompletely understood. This study aimed to identify the associations of metabolites with sarcopenia and its components, and to explore metabolic perturbations in older men, who have a higher prevalence of sarcopenia than women. METHODS: We simultaneously measured the concentrations of amino acids, carnitine, acylcarnitines, and lysophosphatidylcholines (LPCs) in serum samples from a cross-sectional study of 246 Chinese older men, using targeted metabolomics. Sarcopenia and its components, including skeletal muscle index (SMI), 6-m gait speed, and handgrip strength were assessed according to the algorithm of the Asian Working Group for Sarcopenia criteria. Associations were determined by univariate and multivariate analyses. RESULTS: Sixty-five (26.4%) older men with sarcopenia and 181 (73.6%) without sarcopenia were included in the study. The level of isovalerylcarnitine (C5) was associated with the presence of sarcopenia and SMI. Regarding the overlapped metabolites for muscle parameters, among ten metabolites associated with muscle mass, six metabolites including leucine, octanoyl-L-carnitine (C8), decanoyl-L-carnitine (C10), dodecanoyl-L-carnitine (C12) and tetradecanoyl-L-carnitine (C14), and LPC18:2 were associated with handgrip strength, and three of which (C12, C14, and LPC18:2) were also associated with gait speed. Specifically, tryptophan was positively associated and glycine was negatively associated with handgrip strength, while glutamate was positively correlated with gait speed. Isoleucine, branched chain amino acids, and LPC16:0 were positively associated with SMI. Moreover, the levels of LPC 16:0,18:2 and 18:0 contributed significantly to the model discriminating between older men with and without sarcopenia, whereas there were no significant associations for other amino acids, acylcarnitines, and LPC lipids. CONCLUSIONS: These results showed that specific and overlapped metabolites are associated with sarcopenic parameters in older men. This study highlights the potential roles of acylcarnitines and LPCs in sarcopenia and its components, which may provide valuable information regarding the pathogenesis and management of sarcopenia.

Specific Metabolites Involved in Antioxidation and Mitochondrial Function Are Correlated With Frailty in Elderly Men.

BACKGROUND: As an age-related syndrome, frailty may play a central role in poor health among older adults. Sarcopenia overlaps with the physical domain of frailty, and most existing studies have analyzed the associated factors of frailty and sarcopenia as an isolated state. Perturbations in metabolism may play an important role in the presence of frailty or sarcopenia; however, the metabolites associated with frailty, especially overlapping with sarcopenia remain unclear. In this study, we aimed to explore whether amino acids, carnitines, acylcarnitines and lysophosphatidylcholines, as specific panels, are significantly correlated with frailty, especially overlapping with sarcopenia, to gain insight into potential biomarkers and possible biological mechanisms and to facilitate their management. METHODS: We applied a targeted high-performance liquid chromatography-tandem mass spectrometry approach in serum samples from 246 Chinese older men (age 79.2 ± 7.8 years) with frailty (n = 150), non-frailty (n = 96), frailty and sarcopenia (n = 52), non-frail and non-sarcopenic control (n = 85). Frailty was evaluated using Freid phenotype criteria, sarcopenia was defined by diagnostic algorithm of Asian Working Group on Sarcopenia, and the participants were diagnosed as frailty and sarcopenia when they met the evaluation criteria of both frailty and sarcopenia. A panel of 29 metabolomic profiles was assayed and included different classes of amino acids, carnitines, acylcarnitines, and lysophosphatidylcholines (LPCs). Multivariate logistic regression was used to screen the metabolic factors contributing to frailty status, and orthogonal partial least squares discriminant analysis was used to explore important factors and distinguish different groups. RESULTS: In older men demonstrating the frail phenotype, amino acid perturbations included lower tryptophan and higher glycine levels. With regard to lipid metabolism, the frailty phenotype was characterized by lower concentrations of isovalerylcarnitine (C5), LPC16:0 and LPC18:2, while higher levels of octanoyl-L-carnitine (C8), decanoyl-L-carnitine (C10), dodecanoyl-L-carnitine (C12) and tetradecanoyl-L-carnitine (C14). After adjusting for several clinical confounders, tryptophan, LPC18:2, LPC 16:0 and C5 were negatively correlated with frailty, and C8 and C12 were positively related to frailty. We preliminarily identified metabolic profiles (LPC16:0, LPC18:2, glycine and tryptophan) that may distinguish older men with frailty from those without frailty. Importantly, a set of serum amino acids and LPCs (LPC16:0, LPC18:2, and tryptophan) was characterized in the metabotype of older adults with an overlap of frailty and sarcopenia. The metabolites that were most discriminating of frailty status implied that the underlying mechanism might be involved in antioxidation and mitochondrial dysfunction. CONCLUSIONS: These present metabolic analyses may provide valuable information on the potential biomarkers and possible biological mechanisms of frailty, and overlapping sarcopenia. The findings obtained may offer insight into their management in older adults.

A Bimetallic Nanozyme with Cascade Effect for Synergistic Therapy of Cancer.

Novel nanocomposites were constructed through encapsulation of Au nanoparticles and Ru nanoparticles into dendritic mesoporous silica (DMSN-Au-Ru NPs). These exhibit improved effects due to a cascade catalytic ability for the synergistic therapy of cancer. Au nanoparticles with glucose oxidase-like properties were found to catalyze the oxidation of glucose to produce H2 O2 , while Ru nanoparticles could decompose H2 O2 and produce toxic 1 O2 for improved photodynamic therapy (PDT). In addition, the nanocomposites were found to have good photothermal performance under irradiation by near-infrared (NIR) light. Both in vitro and in vivo experiments show that the nanocomposites have good therapeutic effects due to the cascade catalytic effect and synergistic effect. These findings provide an effective way to design a new generation of nanodrugs for highly efficient cancer treatment.

Selenium Vacancy Engineering Using Bi2Se3 Nanodots for Boosting Highly Efficient Photonic Hyperthermia.

Despite bismuth-based energy conversion nanomaterials having attracted extensive attention for nanomedicine, the nanomaterials suffer from major shortcomings including low tumor accumulation, long internal retention time, and undesirable photothermal conversion efficiency (PCE). To combat these challenges, bovine serum albumin and folic acid co-modified Bi2Se3 nanomedicine with rich selenium vacancies (abbreviated as VSe-BS) was fabricated for the second near-infrared (NIR-II) light-triggered photonic hyperthermia. More importantly, selenium vacancies on the crystal planes (0 1 5) and (0 1 11) of VSe-BS with similar formation energies could be distinctively observed via aberration-corrected scanning transmission electron microscopy images. The defect engineering endows VSe-BS with enhanced conductivity, making VSe-BS possess outstanding PCE (54.1%) in the NIR-II biowindow and desirable photoacoustic imaging performance. Tumor ablation studies indicate that VSe-BS possesses satisfactory therapeutic outcomes triggered by NIR-II light. These findings give rise to inspiration for further broadening the biological applications of defect engineering bismuth-based nanomaterials.