Global contribution of invertebrates to forest litter decomposition.

Forest litter decomposition is an essential component of global carbon and nutrient turnover. Invertebrates play important roles in litter decomposition, but the regional pattern of their effects is poorly understood. We examined 476 case studies across 93 sites and performed a meta-analysis to estimate regional effects of invertebrates on forest litter decomposition. We then assessed how invertebrate diversity, climate and soil pH drive regional variations in invertebrate-mediated decomposition. We found that (1) invertebrate contributions to litter decomposition are 1.4 times higher in tropical and subtropical forests than in forests elsewhere, with an overall contribution of 31% to global forest litter decomposition; and (2) termite diversity, together with warm, humid and acidic environments in the tropics and subtropics are positively associated with forest litter decomposition by invertebrates. Our results demonstrate the significant difference in invertebrate effects on mediating forest litter decomposition among regions. We demonstrate, also, the significance of termites in driving litter mass loss in the tropics and subtropics. These results are particularly pertinent in the tropics and subtropics where climate change and human disturbance threaten invertebrate biodiversity and the ecosystem services it provides.

Lessons From the Coronavirus Disease Experience: Research Participant and Staff Satisfaction With Remote Cognitive Evaluations.

OBJECTIVE: In New York City in 2020 the pandemic shut down in-person research. Icahn School of Medicine's Alzheimer's Disease Research Center transitioned longitudinal evaluations from in-person to telephone to enhance equity of access. We assessed diverse research participants' and clinical research coordinators' (CRC) satisfaction with remote evaluation and examined sociodemographic, cognitive, and behavioral factors that might impact satisfaction. METHODS: Data collected: 241 participants with Clinical Dementia Rating (CDR) = 0/0.5 (3/2020 to 6/2021). A Telehealth Satisfaction Questionnaire for CRCs and participants was administered at the end of remote evaluations. We compared Telehealth Satisfaction Questionnaire items by CDR and Geriatric Depression Scale. RESULTS: Participants' mean age was 78.4, 61.4% were females, 16.2% were Hispanic, 17.1% Asian, 15.8% were non-Hispanic black, and 72.6% CDR = 0. Participant satisfaction was high [14.1 ± 1.4 (out of 15)] but was lower among those with depression. CRC satisfaction was high [16.9 ± 1.8 (out of 18)] but was lower concerning the ability to explain the test battery and interact with participants with CDR = 0.5. CONCLUSION: Telephone research assessments provide flexibility in a hybrid model. They offer equitable access to research participation for those who do not use computer technology and may promote the retention of diverse elderly research participants.

Discovery of novel pyridone-benzamide derivatives possessing a 1-methyl-2-benzimidazolinone moiety as potent EZH2 inhibitors for the treatment of B-cell lymphomas.

Enhancer of zeste homolog 2 (EZH2) is a promising therapeutic target for diffuse large B-cell lymphoma. In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability. After the assessment of the structure-activity relationship at enzymatic and cellular levels, compound N40 was identified. Biochemical assays showed that compound N40 (IC50 = 0.32 nM) exhibited superior inhibitory activity against EZH2 WT, compared with 1 (IC50 = 1.20 nM), and high potency against EZH2 Y641 mutants (EZH2 Y641F, IC50 = 0.03 nM; EZH2 Y641N, IC50 = 0.08 nM), which were approximately 10-fold more active than those of 1 (EZH2 Y641F, IC50 = 0.37 nM; EZH2 Y641N, IC50 = 0.85 nM). Furthermore, compound N40 (IC50 = 3.52 ±â€¯1.23 nM) effectively inhibited the proliferation of Karpas-422 cells and was more potent than 1 (IC50 = 35.01 ±â€¯1.28 nM). Further cellular experiments showed that N40 arrested Karpas-422 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Moreover, N40 inhibited the trimethylation of lysine 27 on histone H3 (H3K27Me3) in Karpas-422 cells bearing the EZH2 Y641N mutant. Additionally, N40 (T1/2 = 177.69 min) showed improved metabolic stability in human liver microsomes compared with 1 (T1/2 = 7.97 min). Our findings suggest N40 as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop N40.

The use of subjective cognitive complaints for detecting mild cognitive impairment in older adults across cultural and linguistic groups: A comparison of the Cognitive Function Instrument to the Montreal Cognitive Assessment.

INTRODUCTION: This pilot study aims to explore the psychometric properties of the Cognitive Function Instrument (CFI) as a measure of subjective cognitive complaints (SCC) and its performance in distinguishing mild cognitive impairment (MCI) from normal control (NC) compared to an objective cognitive screen (Montreal Cognitive Assessment [MoCA]). METHODS: One hundred ninety-four community-dwelling non-demented older adults with racial/ethnic diversity were included. Unidimensionality and internal consistency of the CFI were examined using factor analysis, Cronbach's alpha, and McDonald's omega. Logistic regression models and receiver operating characteristic (ROC) analysis were used to examine the performance of CFI. RESULTS: The CFI demonstrated adequate internal consistency; however, the fit for a unidimensional model was suboptimal. The CFI distinguished MCI from NC alone or in combination with MoCA. ROC analysis showed comparable performance of the CFI and the MoCA. DISCUSSION: Our findings support the use of CFI as a brief and easy-to-use screen to detect MCI in culturally/linguistically diverse older adults. HIGHLIGHT: What is the key scientific question or problem of central interest of the paper? Subjective cognitive complaints (SCCs) are considered the earliest sign of dementia in older adults. However, it is unclear if SCC are equivalent in different cultures. The Cognitive Function Instrument (CFI) is a 14-item measure of SCC. This study provides pilot data suggesting that CFI is sensitive for detecting mild cognitive impairment in a cohort of older adults with racial/ethnic diversity. Comparing performance, CFI demonstrates comparable sensitivity to the Montreal Cognitive Assessment, an objective cognitive screening test. Overall, SCC may provide a non-invasive, easy-to-use method to flag possible cognitive impairment in both research and clinical settings.

The 32-Item Multilingual Naming Test: Cultural and Linguistic Biases in Monolingual Chinese-Speaking Older Adults.

OBJECTIVES: This study describes the performance of the Multilingual Naming Test (MINT) by Chinese American older adults who are monolingual Chinese speakers. An attempt was also made to identify items that could introduce bias and warrant attention in future investigation. METHODS: The MINT was administered to 67 monolingual Chinese older adults as part of the standard dementia evaluation at the Alzheimer's Disease Research Center (ADRC) at the Icahn School of Medicine at Mount Sinai (ISMMS), New York, USA. A diagnosis of normal cognition (n = 38), mild cognitive impairment (n = 12), and dementia (n = 17) was assigned to all participants at clinical consensus conferences using criterion sheets developed at the ADRC at ISMMS. RESULTS: MINT scores were negatively correlated with age and positively correlated with education, showing sensitivity to demographic factors. One item, butterfly, showed no variations in responses across diagnostic groups. Inclusion of responses from different regions of China changed the answers from "incorrect" to "correct" on 20 items. The last five items, porthole, anvil, mortar, pestle, and axle, yielded a high nonresponse rate, with more than 70% of participants responding with "I don't know." Four items, funnel, witch, seesaw, and wig, were not ordered with respect to item difficulty in the Chinese language. Two items, gauge and witch, were identified as culturally biased for the monolingual group. CONCLUSIONS: Our study highlights the cultural and linguistic differences that might influence the test performance. Future studies are needed to revise the MINT using more universally recognized items of similar word frequency across different cultural and linguistic groups.

Evaluating the Beijing Version of Montreal Cognitive Assessment for Identification of Cognitive Impairment in Monolingual Chinese American Older Adults.

Objective: This study aims to evaluate the performance of a Chinese version of the Montreal Cognitive Assessment (MoCA) as a screener to detect mild cognitive impairment (MCI) and dementia from normal cognition in the monolingual Chinese-speaking immigrant population. Method: A cohort of 176 Chinese-speaking older adults from the National Alzheimer's Coordinating Center Uniform Data Set is used for analysis. We explore the impact of demographic variables on MoCA performance and calculate the optimal cutoffs for the detection of MCI and dementia from normal cognition with appropriate demographic adjustment. Results: MoCA performance is predicted by age and education independent of clinical diagnoses, but not by sex, years of living in the U.S., or primary Chinese dialect spoken (i.e., Mandarin vs. Cantonese). With adjustment and stratification for education and age, we identify optimal cutoff scores to detect MCI and dementia, respectively, in this population. These optimal cutoff scores are different from the established scores for non-Chinese-speaking populations residing in the U.S. Conclusions: Our findings suggest that the Chinese version of MoCA is a valid screener to detect cognitive decline in older Chinese-speaking immigrants in the U.S. They also highlight the need for population-based cutoff scores with appropriate considerations for demographic variables.

Smartphone ownership and usage in Chinese- and English-speaking older adults.

BACKGROUND: Data collection by smartphone is becoming more widespread in healthcare research. Previous studies reported racial/ethnical differences in the use of digital health technology. However, cross-language group comparison (Chinese- and English-speaking older adults) were not performed in these studies. This project will expand to smartphone technology use in diverse older populations with a focus on Chinese American older adults who are monolingual Chinese-speakers. METHOD: The Alzheimer's Disease Research Center (ADRC) at Icahn School of Medicine at Mount Sinai (ISMMS) evaluates diverse older populations using National Alzheimer's Coordinating Center's Uniform Data Set (NACC UDS). The UDS has different language versions, including English and Chinese. The evaluation includes a medical examination, cognitive assessments, and a research blood draw. Smartphone ownership and usage were captured using a local questionnaire developed by our ADRC. The questionnaire, available in English and Chinese, was administered by our ADRC coordinators during the COVID-19 pandemic. Multivariate analysis of variance (MANOVA) was used to examine differences in technology ownership and usages between the two language groups, while controlling for age, gender, education, and cognitive status (measured by Clinical Dementia Rating). RESULT: 33 Chinese- and 117 English-speaking older adults who received a diagnosis of normal cognition or mild cognitive impairment at consensus were included in the data analysis. Results reveal a high prevalence of smartphone ownership in our Chinese- (100%) and English-speaking older participants (86.3%). Participants in both language groups use mobile technology for a wide range of purposes, such as getting news and other information (Chinese=90.9%; English=87.2%), sending/receiving text (Chinese=97.0%; English=96.6%), watching videos/TV shows (Chinese=78.8%; English=69.2%), and taking classes (Chinese=57.5%; English=57.3%). However, Chinese-speaking older adults were less likely than English-speaking older adults to use mobile technology to post their own reviews or comments online (Chinese=9.1%; English=39.3%, p=0.001), download or purchase an app (Chinese=21.2%; English=70.9%, p<0.001), track health/ fitness via apps/website (Chinese=12.1%; English=47.9%, p<0.001) and manage/receive medical care (Chinese=15.2%; English=67.5%, p<0.001). CONCLUSION: Our findings highlight potential barriers to smartphone usage in Chinese American older adults with limited English proficiency. The results have implications for how smartphone technology can be used in clinical practice and aging research.

Cognitive test battery for evaluating elderly Chinese Americans.

ABSTRACTObjectives:This study aimed to determine the diagnostic utility of a Chinese test battery for evaluating cognitive loss in elderly Chinese Americans. METHODS: Data from a pilot study at the Mount Sinai Alzheimer's Disease Research Center was examined. All participants were > 65 years old, primarily Chinese speaking, with adequate sensorimotor capacity to complete cognitive tests. A research diagnosis of normal mild cognitive impairment (MCI) or Alzheimer's disease (AD) was assigned to each participant in consensus conference. Composite scores were created to summarize test performance on overall cognition, memory, attention executive function, and language. Multivariable logistic regression models were used to assess the sensitivity of each cognitive domain for discriminating three diagnostic categories. Adjustment was made for demographic variables (i. e., age, gender, education, primary language, and years living in the USA). RESULTS: The sample included 67 normal, 37 MCI, and 12 AD participants. Performance in overall cognition, memory, and attention executive function was significantly worse in AD than in MCI, and performance in MCI was worse than in normal controls. Language performance followed a similar pattern, but differences did not achieve statistical significance among the three diagnostic groups. CONCLUSIONS: This study highlights the need for cognitive assessment in elderly Chinese immigrants.

Metabolomic analysis of insulin resistance across different mouse strains and diets.

Insulin resistance is a major risk factor for many diseases. However, its underlying mechanism remains unclear in part because it is triggered by a complex relationship between multiple factors, including genes and the environment. Here, we used metabolomics combined with computational methods to identify factors that classified insulin resistance across individual mice derived from three different mouse strains fed two different diets. Three inbred ILSXISS strains were fed high-fat or chow diets and subjected to metabolic phenotyping and metabolomics analysis of skeletal muscle. There was significant metabolic heterogeneity between strains, diets, and individual animals. Distinct metabolites were changed with insulin resistance, diet, and between strains. Computational analysis revealed 113 metabolites that were correlated with metabolic phenotypes. Using these 113 metabolites, combined with machine learning to segregate mice based on insulin sensitivity, we identified C22:1-CoA, C2-carnitine, and C16-ceramide as the best classifiers. Strikingly, when these three metabolites were combined into one signature, they classified mice based on insulin sensitivity more accurately than each metabolite on its own or other published metabolic signatures. Furthermore, C22:1-CoA was 2.3-fold higher in insulin-resistant mice and correlated significantly with insulin resistance. We have identified a metabolomic signature composed of three functionally unrelated metabolites that accurately predicts whole-body insulin sensitivity across three mouse strains. These data indicate the power of simultaneous analysis of individual, genetic, and environmental variance in mice for identifying novel factors that accurately predict metabolic phenotypes like whole-body insulin sensitivity.

Repurposing matrine for the treatment of hepatosteatosis and associated disorders in glucose homeostasis in mice.

The present study investigated the efficacy of the hepatoprotective drug matrine (Mtr) for its new application for hepatosteatosis and associated disorders in glucose homeostasis. The study was performed in two nutritional models of hepatosteatosis in mice with various abnormal glucose homeostasis: (1) high-fructose diet (HFru) induced hepatosteatosis and glucose intolerance from hepatic, and (2) hepatosteatosis and hyperglycemia induced by high-fat (HF) diet in combination with low doses of streptozotocin (STZ). Administration of Mtr (100 mg/kg every day in diet for 4 weeks) abolished HFru-induced hepatosteatosis and glucose intolerance. These effects were associated with the inhibition of HFru-stimulated de novo lipogenesis (DNL) without altering hepatic fatty acid oxidation. Further investigation revealed that HFru-induced endoplasmic reticulum (ER) stress was inhibited, whereas heat-shock protein 72 (an inducible chaperon protein) was increased by Mtr. In a type 2 diabetic model induced by HF-STZ, Mtr reduced hepatosteatosis and improved attenuated hyperglycemia. The hepatoprotective drug Mtr may be repurposed for the treatment of hepatosteatosis and associated disorders in glucose homeostasis. The inhibition of ER stress associated DNL and fatty acid influx appears to play an important role in these metabolic effects.

Endoplasmic reticulum stress up-regulates Nedd4-2 to induce autophagy.

The accumulation of unfolded proteins within the endoplasmic reticulum (ER) causes ER stress and activation of unfolded protein response (UPR). This response can trigger ER-associated degradation and autophagy, which clear unfolded proteins and restore protein homeostasis. Recently, it has become clear that ubiquitination plays an important role in the regulation of autophagy. In the present study, we investigated how the E3 ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4-2 (Nedd4-2) interacts with ER stress and autophagy. In mice, we found that an increase in the expression of Nedd4-2, which was concomitant with the activation of the UPR and autophagy, was caused by a prolonged high-fructose and high-fat diet that induces ER stress in the liver. Pharmacologic induction of ER stress also led to an increase in Nedd4-2 expression in cultured cells, which was coincident with UPR and autophagy activation. The inhibition of inositol-requiring enzyme 1 significantly suppressed Nedd4-2 expression. Moreover, increased Nedd4-2 expression in vivo was closely associated with the activation of inositol-requiring enzyme 1 and increased expression of the spliced form of X-box binding protein 1. Furthermore, knockdown of Nedd4-2 in cultured cells suppressed both basal autophagy and ER stress-induced autophagy, whereas overexpression of Nedd4-2-induced autophagy. Taken together, our findings provide evidence that Nedd4-2 is up-regulated in response to ER stress by the spliced form of X-box binding protein 1 and that this is important in the induction of an appropriate autophagic response.-Wang, H. Sun, R.-Q., Camera, D., Zeng, X.-Y., Jo, E., Chan, S. M. H., Herbert, T. P., Molero, J. C., Ye, J.-M. Endoplasmic reticulum stress up-regulates Nedd4-2 to induce autophagy.

IRE1 impairs insulin signaling transduction of fructose-fed mice via JNK independent of excess lipid.

The unfolded protein response (UPR) pathways have been implicated in the development of hepatic insulin resistance during high fructose (HFru) feeding. The present study investigated their roles in initiating impaired insulin signaling transduction in the liver induced by HFru feeding in mice. HFru feeding resulted in hepatic steatosis, increased de novo lipogenesis and activation of two arms of the UPR pathways (IRE1/XBP1 and PERK/eIF2α) in similar patterns from 3days to 8weeks. In order to identify the earliest trigger of impaired insulin signaling in the liver, we fed mice a HFru diet for one day and revealed that only the IRE1 branch was activated (by 2-fold) and insulin-mediated Akt phosphorylation was blunted (~25%) in the liver. There were significant increases in phosphorylation of JNK (~50%) and IRS at serine site (~50%), protein content of ACC and FAS (up to 2.5-fold) and triglyceride level (2-fold) in liver (but not in muscle or fat). Blocking IRE1 activity abolished increases in JNK activity, IRS serine phosphorylation and protected insulin-stimulated Akt phosphorylation without altering hepatic steatosis or PKCε activity, a key link between lipids and insulin resistance. Our findings together suggest that activation of IRE1-JNK pathway is a key linker of impaired hepatic insulin signaling transduction induced by HFru feeding.

Fenofibrate insulates diacylglycerol in lipid droplet/ER and preserves insulin signaling transduction in the liver of high fat fed mice.

Hepatic steatosis is often associated with insulin resistance as a hallmark of the metabolic syndrome in the liver. The present study investigated the effects of PPARα activation induced by fenofibrate (FB) on the relationship of insulin resistance and hepatic steatosis in mice fed a high-fat (HF) diet, which increases lipid influx into the liver. Mice were fed HF diet to induce insulin resistance and hepatic steatosis with or without FB. FB activated PPARα and ameliorated HF diet-induced glucose intolerance and hepatic insulin resistance without altering either hepatic steatosis or inflammation signaling (JNK or IKK). Interestingly, FB treatment simultaneously increased fatty acid (FA) synthesis (50%) and oxidation (66%, both p<0.01) into intermediate lipid metabolites, suggesting a FA oxidation-synthesis cycling in operation. Associated with these effects, diacylglycerols (DAGs) were sequestered within the lipid droplet/ER compartment, thus reducing their deposition in the cellular membrane, which is known to impair insulin signal transduction. These findings suggest that the reduction in membrane DAGs (rather than total hepatic steatosis) may be critical for the protection by fenofibrate-induced PPARα activation against hepatic insulin resistance induced by dietary fat.

Liver glycogen in type 2 diabetic mice is randomly branched as enlarged aggregates with blunted glucose release.

Glycogen is a vital highly branched polymer of glucose that is essential for blood glucose homeostasis. In this article, the structure of liver glycogen from mice is investigated with respect to size distributions, degradation kinetics, and branching structure, complemented by a comparison of normal and diabetic liver glycogen. This is done to screen for differences that may result from disease. Glycogen α-particle (diameter ∼ 150 nm) and ß-particle (diameter ∼ 25 nm) size distributions are reported, along with in vitro γ-amylase degradation experiments, and a small angle X-ray scattering analysis of mouse ß-particles. Type 2 diabetic liver glycogen upon extraction was found to be present as large loosely bound, aggregates, not present in normal livers. Liver glycogen was found to aggregate in vitro over a period of 20 h, and particle size is shown to be related to rate of glucose release, allowing a structure-function relationship to be inferred for the tissue specific distribution of particle types. Application of branching theories to small angle X-ray scattering data for mouse ß-particles revealed these particles to be randomly branched polymers, not fractal polymers. Together, this article shows that type 2 diabetic liver glycogen is present as large aggregates in mice, which may contribute to the inflexibility of interconversion between glucose and glycogen in type 2 diabetes, and further that glycogen particles are randomly branched with a size that is related to the rate of glucose release.

Recruiting US Chinese Elders Into Clinical Research for Dementia.

PURPOSE: This study described and evaluated the rapid recruitment of elderly Chinese into clinical research at the Mount Sinai Alzheimer's Disease Research Center (MSADRC). DESIGN AND METHODS: Methods of publicizing the study included lectures to local senior centers/churches and publications in local Chinese newspapers. The amount of time and success of these methods were evaluated. A "go to them" model of evaluation was used to enable participants to complete the study visit at locations where they were comfortable. RESULTS: From January to December 2015, we recruited 98 participants aged 65 years or older who primarily speak Mandarin/Cantonese and reside in New York. The mean age and years of education was 73.93±6.34 and 12.79±4.58, respectively. The majority of participants were female (65.3%) and primarily Mandarin speaking (53.1%). Of all enrollees, 54.1% were recruited from community lectures, 29.6% through newspapers, 10.2% through word of mouth, and 6.1% from our clinical services. About 40.8% of participants underwent evaluations at the MSADRC, 44.9% at local senior centers/churches, and 14.3% at home. IMPLICATIONS: Given that the majority of our participants had low English proficiency, the use of bilingual recruiters probably allowed us to overcome the language barrier, facilitating recruitment. Our "go to them" model of evaluation is another important factor contributing to our successful recruitment.

Relationship of neutrophil/lymphocyte ratio with cerebral small vessel disease and its common imaging markers.

BACKGROUND: High neutrophil/lymphocyte ratio (NLR) is associated with poor prognosis in ischemic stroke. However, the role of NLR in cerebral small vessel disease (CSVD) is controversial. Herein, we evaluated the value of NLR in identifying CSVD and its relationship with the common imaging markers of CSVD. METHODS: A total of 667 patients were enrolled in this study, including 368 in the CSVD group and 299 in the non-CSVD group. Clinical, laboratory, and imaging data were collected. The relationship of NLR with CSVD and common imaging markers of CSVD were analyzed with univariate and multivariate logistic regression analysis. The predictive value of NLR was assessed with the receiver operating characteristic curve. RESULTS: NLR (odds ratio [OR] = 1.929, 95% confidence interval [CI] = 1.599-2.327, p < .001) was an independent risk factor for CSVD. NLR was also independently associated with moderate to severe white matter hyperintensity (WMH) (OR = 2.136, 95% CI = 1.768-2.580, p < .001), moderate to severe periventricular WMH (OR = 2.138, 95% CI = 1.771-2.579, p < .001), and moderate to severe deep WMH (OR = 1.654, 95% CI = 1.438-1.902, p < .001), moderately to severely enlarged perivascular spaces (EPVS) (OR = 1.248, 95% CI = 1.110-1.402, p < .001), moderately to severely EPVS in the basal ganglia (OR = 1.136, 95% CI = 1.012-1.275, p = .030), and moderately to severely EPVS in the centrum semiovale (OR = 1.140, 95% CI = 1.027-1.266, p = .014). However, NLR was not statistically significantly associated with lacune. The optimal cutoff point of NLR in predicting CSVD was 2.47, with sensitivity and specificity of 84.2% and 66.9%, respectively (p < .01). The diagnostic effect was maximized when NLR was combined with other risk factors. CONCLUSIONS: NLR is an independent risk factor for CSVD and is independently associated with common imaging markers of CSVD. NLR may serve as a valid and convenient biomarker for assessing CSVD.

Establishing subdivisions of M1 stage nasopharyngeal carcinoma based on decision tree classification: A multicenter retrospective study.

OBJECTIVES: To meet the demand for personalized treatment, effective stratification of patients with metastatic nasopharyngeal carcinoma (mNPC) is essential. Hence, our study aimed to establish an M1 subdivision for prognostic prediction and treatment planning in patients with mNPC. MATERIALS AND METHODS: This study included 1239 patients with mNPC from three medical centers divided into the synchronous mNPC cohort (smNPC, n = 556) to establish an M1 stage subdivision and the metachronous mNPC cohort (mmNPC, n = 683) to validate this subdivision. The primary endpoint was overall survival. Univariate and multivariate Cox analyses identified covariates for the decision-tree model, proposing an M1 subdivision. Model performance was evaluated using time-dependent receiver operating characteristic curves, Harrell's concordance index, calibration plots, and decision curve analyses. RESULTS: The proposed M1 subdivisions were M1a (≤5 metastatic lesions), M1b (>5 metastatic lesions + absent liver metastases), and M1c (>5 metastatic lesions + existing liver metastases) with median OS of 34, 22, and 13 months, respectively (p < 0.001). This M1 subdivision demonstrated superior discrimination (C-index = 0.698; 3-year AUC = 0.707) and clinical utility over those of existing staging systems. Calibration curves exhibited satisfactory agreement between predictions and actual observations. Internal and mmNPC cohort validation confirmed the robustness. Survival benefits from local metastatic treatment were observed in M1a, while immunotherapy improved survival in patients with M1b and M1c disease. CONCLUSION: This novel M1 staging strategy provides a refined approach for prognostic prediction and treatment planning in patients with mNPC, emphasizing the potential benefits of local and immunotherapeutic interventions based on individualized risk stratification.

Efficacy of metastatic lesion radiotherapy in patients with metastatic nasopharyngeal carcinoma: A multicenter retrospective study.

OBJECTIVE: We investigated the efficacy of metastatic lesion radiotherapy (MLRT) in patients with metastatic nasopharyngeal carcinoma (mNPC). MATERIALS AND METHODS: Patients with mNPC from three institutions were included in this study. Propensity score matching (PSM) was employed to ensure comparability between patient groups. Overall survival (OS) rates were assessed using the Kaplan-Meier method and compared using the log-rank test. Prognostic factors were identified using univariate and multivariate Cox hazard analyses. Subgroup analyses were conducted to assess the effects of MLRT on specific patient populations. RESULTS: We analyzed data from 1157 patients with mNPC. Patients who received MLRT had significantly better OS than those who did not, both in the original (28 vs. 21 months) and PSM cohorts (26 vs. 23 months). MLRT was identified as an independent favorable predictor of OS in multivariate analyses, with hazard ratios of 0.67. The subgroup analysis results indicated that radiotherapy effectively treated liver, lung, and bone metastatic lesions, particularly in patients with a limited tumor burden. Higher total radiation doses of MLRT (biologically effective dose (BED) ≥ 56 Gy) were associated with improved OS, while neither radiation technique nor dose fractionation independently influenced prognosis. CONCLUSIONS: MLRT offers survival advantages to patients diagnosed with mNPC. Patients with limited metastatic burden derive the most benefit from MLRT, and the recommended regimen for MLRT is a minimum BED of 56 Gy for optimal outcomes.

Agents for the Treatment of Gout: Current Advances and Future Perspectives.

Gout is characterized by hyperuricemia and the deposition of monosodium urate (MSU) crystals around joints. Despite the availability of several drugs on the market, its treatment remains challenging owing to the notable side effects, such as hepatorenal toxicity and cardiovascular complications, that are associated with most existing agents. This perspective aims to summarize the current research progress in the development of antigout agents, particularly focusing on xanthine oxidase (XO) and urate anion transporter 1 (URAT1) inhibitors from a medicinal chemistry viewpoint and their preliminary structure-activity relationships (SARs). This perspective provides valuable insights and theoretical guidance to medicinal chemists for the discovery of antigout agents with novel chemical structures, better efficiency, and lower toxicity.

Earthworms increase forest litter mass loss irrespective of deposited compounds - A field manipulation experiment in subtropical forests.

Earthworms modulate carbon and nitrogen cycling in terrestrial ecosystems, but their effect may be compromised by the deposition of pollutants from industrial emissions. However, studies investigating how deposited compounds affect the role of earthworms in carbon cycling such as litter decomposition are lacking, although the interactions of earthworms and deposited compounds are important for understanding the impact of pollutants on ecosystems and the potential of earthworms in bioremediation. We performed a 365-day in situ litterbag decomposition experiment in a deciduous (Quercus variabilis) and coniferous (Pinus massoniana) forest in southeast China. We manipulated nitrogen (N), sodium (Na), and polycyclic aromatic hydrocarbons (PAHs) as model compounds during litter decomposition with and without earthworms (Eisenia fetida). After one year, N, Na, and PAH all slowed down litter mass loss, with the effects of Na being the strongest. By contrast, E. fetida generally increased litter mass loss, and the positive effects were uniformly maintained irrespective of the type of compounds added. However, the pathways to how earthworms increased litter mass loss varied among the compounds added and the two forests studied. As indicated by structural equation modeling, earthworms mitigated the negative effects of deposited compounds by directly increasing litter mass loss and indirectly increasing soil pH and microbial biomass. Overall, the results indicate that the acceleration of litter mass loss by earthworms is little affected by deposited compounds, and that earthworms have the potential to mitigate negative impacts of pollutants on litter decomposition and ecosystem processes.