Combining lymph node ratio to develop prognostic models for postoperative gastric neuroendocrine neoplasm patients.

BACKGROUND: Lymph node ratio (LNR) was demonstrated to play a crucial role in the prognosis of many tumors. However, research concerning the prognostic value of LNR in postoperative gastric neuroendocrine neoplasm (NEN) patients was limited. AIM: To explore the prognostic value of LNR in postoperative gastric NEN patients and to combine LNR to develop prognostic models. METHODS: A total of 286 patients from the Surveillance, Epidemiology, and End Results database were divided into the training set and validation set at a ratio of 8:2. 92 patients from the First Affiliated Hospital of Soochow University in China were designated as a test set. Cox regression analysis was used to explore the relationship between LNR and disease-specific survival (DSS) of gastric NEN patients. Random survival forest (RSF) algorithm and Cox proportional hazards (CoxPH) analysis were applied to develop models to predict DSS respectively, and compared with the 8th edition American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging. RESULTS: Multivariate analyses indicated that LNR was an independent prognostic factor for postoperative gastric NEN patients and a higher LNR was accompanied by a higher risk of death. The RSF model exhibited the best performance in predicting DSS, with the C-index in the test set being 0.769 [95% confidence interval (CI): 0.691-0.846] outperforming the CoxPH model (0.744, 95%CI: 0.665-0.822) and the 8th edition AJCC TNM staging (0.723, 95%CI: 0.613-0.833). The calibration curves and decision curve analysis (DCA) demonstrated the RSF model had good calibration and clinical benefits. Furthermore, the RSF model could perform risk stratification and individual prognosis prediction effectively. CONCLUSION: A higher LNR indicated a lower DSS in postoperative gastric NEN patients. The RSF model outperformed the CoxPH model and the 8th edition AJCC TNM staging in the test set, showing potential in clinical practice.

Predicting hepatocellular carcinoma: A new non-invasive model based on shear wave elastography.

BACKGROUND: Integrating conventional ultrasound features with 2D shear wave elastography (2D-SWE) can potentially enhance preoperative hepatocellular carcinoma (HCC) predictions. AIM: To develop a 2D-SWE-based predictive model for preoperative identification of HCC. METHODS: A retrospective analysis of 884 patients who underwent liver resection and pathology evaluation from February 2021 to August 2023 was conducted at the Oriental Hepatobiliary Surgery Hospital. The patients were divided into the modeling group (n = 720) and the control group (n = 164). The study included conventional ultrasound, 2D-SWE, and preoperative laboratory tests. Multiple logistic regression was used to identify independent predictive factors for malignant liver lesions, which were then depicted as nomograms. RESULTS: In the modeling group analysis, maximal elasticity (Emax) of tumors and their peripheries, platelet count, cirrhosis, and blood flow were independent risk indicators for malignancies. These factors yielded an area under the curve of 0.77 (95% confidence interval: 0.73-0.81) with 84% sensitivity and 61% specificity. The model demonstrated good calibration in both the construction and validation cohorts, as shown by the calibration graph and Hosmer-Lemeshow test (P = 0.683 and P = 0.658, respectively). Additionally, the mean elasticity (Emean) of the tumor periphery was identified as a risk factor for microvascular invasion (MVI) in malignant liver tumors (P = 0.003). Patients receiving antiviral treatment differed significantly in platelet count (P = 0.002), Emax of tumors (P = 0.033), Emean of tumors (P = 0.042), Emax at tumor periphery (P < 0.001), and Emean at tumor periphery (P = 0.003). CONCLUSION: 2D-SWE's hardness value serves as a valuable marker for enhancing the preoperative diagnosis of malignant liver lesions, correlating significantly with MVI and antiviral treatment efficacy.

[Non-targeted renal metabolomics reveals multi-target effects of Dahuang Zhechong Pills on renal aging in rats].

This study aims to observe the effects of the traditional Chinese medicine prescription Dahuang Zhechong Pills(DHZCP on renal aging and explore its potential multi-target effects. Rats were assigned into the normal, model, DHZCP, and vitamin E(VE)groups. Firstly, the rat model of D-galactose(D-gal)-induced renal aging was established. During the modeling period, the rats in the 4 groups were administrated with double distilled water, double distilled water, DHZCP suspension, and VE suspension, respectively,by gavage every day. On day 60 of intervention, the indicators of renal aging and injury in rats were measured, including the function,histopathological characteristics, senescence-associated ß-galactosidase( SA-ß-gal) staining, and expression levels of Klotho and proteins associated with cell cycle arrest and senescence-associated secretory phenotype(SASP) in the renal tissue. Moreover, nontargeted metabolomic analysis of the renal tissue was performed for the 4 groups of rats to screen out the potential biomarkers and metabolic pathways. Finally, the signaling pathways of key targets were preliminarily validated. The results showed that DHZCP and VE significantly improved the renal function, histopathological features of renal tubular/interstitial tissue, and degree of SA-ß-gal staining, up-regulated the expression level of Klotho, and down-regulated the expression levels of proteins associated with cell cycle arrest and SASP in the renal tissue of the aging rats. In addition, DHZCP and VE regulated the metabolites in the renal tissue of the aging rats. There were 21 common differential metabolites. Among them, 5 differential metabolites were significantly increased in the aging rats and recovered after DHZCP or VE treatment, and they were involved in the lipid metabolism and energy metabolism pathways. The areas under the curves of the groups in comparison varied within the range of 0. 88-1. DHZCP regulated multiple signaling pathways, such as the adenosine monophosphate-activated protein kinase(AMPK), cyclic guanosine monophosphate-protein kinase G( c GMP-PKG), cyclic adenylic acid( c AMP), phosphatidylinositol-3-kinase-protein kinase B( PI3K-Akt), mammalian target of rapamycin(mTOR), and autophagy signaling pathways. In addition, it affected the multiple metabolic pathways, such as renin secretion, longevity regulation pathway, diabetic cardiomyopathy, and niacin and nicotinamide metabolism. DHZCP and VE significantly up-regulated the expression level of the key proteins in the AMPK signaling pathway in the renal tissue of the aging rats. In all, DHZCP and VE could mitigate renal aging and injury. DHZCP exerted multi-target effects via multiple signaling pathways and metabolic pathways in the kidney, in which the AMPK signaling pathway may be one of the key targets for action.

Mapping of lymph node metastasis from esophageal squamous cell carcinoma after neoadjuvant treatment: a prospective analysis from a high-volume institution in China.

The study aimed to describe the prevalence of lymph node metastases per lymph node station for esophageal squamous cell carcinoma (ESCC) after neoadjuvant treatment. Clinicopathological variables of ESCC patients were retrieved from the prospective database of the Surgical Esophageal Cancer Patient Registry in West China Hospital, Sichuan University. A two-field lymphadenectomy was routinely performed, and an extensive three-field lymphadenectomy was performed if cervical lymph node metastasis was suspected. According to AJCC/UICC 8, lymph node stations were investigated separately. The number of patients with metastatic lymph nodes divided by those who underwent lymph node dissection at that station was used to define the percentage of patients with lymph node metastases. Data are also separately analyzed according to the pathological response of the primary tumor, neoadjuvant treatment regimens, pretreatment tumor length, and tumor location. Between January 2019 and March 2023, 623 patients who underwent neoadjuvant therapy followed by transthoracic esophagectomy were enrolled. Lymph node metastases were found in 212 patients (34.0%) and most frequently seen in lymph nodes along the right recurrent nerve (10.1%, 58/575), paracardial station (11.4%, 67/587), and lymph nodes along the left gastric artery (10.9%, 65/597). For patients with pretreatment tumor length of >4 cm and non-pathological complete response of the primary tumor, the metastatic rate of the right lower cervical paratracheal lymph nodes is 10.9% (10/92) and 10.6% (11/104), respectively. For patients with an upper thoracic tumor, metastatic lymph nodes were most frequently seen along the right recurrent nerve (14.2%, 8/56). For patients with a middle thoracic tumor, metastatic lymph nodes were most commonly seen in the right lower cervical paratracheal lymph nodes (10.3%, 8/78), paracardial lymph nodes (10.2%, 29/285), and lymph nodes along the left gastric artery (10.4%, 30/289). For patients with a lower thoracic tumor, metastatic lymph nodes were most frequently seen in the paracardial station (14.2%, 35/247) and lymph nodes along the left gastric artery (13.1%, 33/252). The study precisely determined the distribution of lymph node metastases in ESCC after neoadjuvant treatment, which may help to optimize the extent of lymphadenectomy in the surgical management of ESCC patients after neoadjuvant therapy.

Spatial - temporal mapping of urine cadmium levels in China during 1980 - 2040: Dietary improvements lower exposure amid rising pollution.

Persistent cadmium exposure poses significant health risks to the Chinese population, underscored by its prevalence as an environmental contaminant. This study leverages a machine-learning model, fed with a comprehensive dataset of environmental and socio-economic factors, to delineate trends in cadmium exposure from 1980 to 2040. We uncovered that urinary cadmium levels peaked at 1.09 µg/g Cr in the mid-2000 s. Encouragingly, a decline is projected to 0.92 µg/g Cr by 2025, tapering further to 0.87 µg/g Cr by 2040. Despite this trend, regions heavily influenced by industrialization, such as Hunan and Guizhou, as well as industrial counties in Jilin, report stubbornly high levels of exposure. Our demographic analysis reveals a higher vulnerability among adults & adolescents over 14, with males displaying elevated cadmium concentrations. Alarmingly, the projected data suggests that by 2040, an estimated 41% of the population will endure exposure beyond the safety threshold set by the European Food Safety Authority. Our research indicates disproportionate cadmium exposure impacts, necessitating targeted interventions and policy reforms to protect vulnerable groups and public health in China.

Cadmium Exposure was Associated with Sex-Specific Thyroid Dysfunction: Consistent Evidence from Two Independent Cross-Sectional Studies Based on Urinary and Blood Cadmium Measurements.

Population-based studies on the association between cadmium (Cd) exposure and thyroid function are limited and have shown conflicting results. Two independent cross-sectional studies using different Cd biomarkers were carried out in six rural areas with different soil Cd levels in China. Thyroid dysfunction was defined based on levels of thyroid stimulating hormone (TSH) and free thyroxine (FT4). Multivariable linear regression, multiple logistic regression, and restrictive cubic splines models were used to estimate the association between Cd and thyroid dysfunction. For both of the two independent studies, higher Cd levels were observed to be associated with lower TSH levels and higher risk of thyroid dysfunction. The negative relationship between urinary Cd and TSH was found in both total participants (ß = - 0.072, p = 0.008) and males (ß = - 0.119, p = 0.020) but not in females; however, the negative relationship between blood Cd and TSH was only found in females (ß = - 0.104, p = 0.024). Higher urinary Cd was associated with higher risk of thyroid dysfunction (OR = 1.77, p = 0.031), while higher blood Cd was associated with higher risk of thyroid dysfunction (OR = 1.95, p = 0.011). Results from the two independent cross-sectional studies consistently suggested that higher Cd levels were associated with sex-specific thyroid dysfunction.

Urinary cadmium levels in China (1982-2021): Regional trends and influential factors.

Despite the significant threat of cadmium exposure in China, a national-level assessment has been conspicuously absent. This study bridges this critical gap by collecting, geospatial analyzing and multivariable regression analyzing published studies on urinary cadmium levels in Chinese from 1982 to 2021. Our research reveals a notable decline trend in cadmium exposure among Chinese populations. However, this trend varies by region, age and gender group, higher levels are seen in the South (1.04 µg/g cr) compared to the North (0.48 µg/g cr), and in adults (1.08 µg/g cr) relative to children (0.33 µg/g cr), with higher levels being more pronounced in females (6.17 µg/g cr). Urinary cadmium is significantly correlated with rice consumption (P < 0.001), while mining activities have been identified as the dominant factor for cadmium exposure in most regions of China, a trend that is evident both in past decades and is expected to continue into the next decade. These findings underscore the need for region-specific environmental and public health strategies, designed to effectively address the distinct cadmium exposure risks in various regions and among different population groups, thus enhancing protection against the adverse effects of cadmium.

Automatic hip osteoarthritis grading with uncertainty estimation from computed tomography using digitally-reconstructed radiographs.

PURPOSE: Progression of hip osteoarthritis (hip OA) leads to pain and disability, likely leading to surgical treatment such as hip arthroplasty at the terminal stage. The severity of hip OA is often classified using the Crowe and Kellgren-Lawrence (KL) classifications. However, as the classification is subjective, we aimed to develop an automated approach to classify the disease severity based on the two grades using digitally-reconstructed radiographs from CT images. METHODS: Automatic grading of the hip OA severity was performed using deep learning-based models. The models were trained to predict the disease grade using two grading schemes, i.e., predicting the Crowe and KL grades separately, and predicting a new ordinal label combining both grades and representing the disease progression of hip OA. The models were trained in classification and regression settings. In addition, the model uncertainty was estimated and validated as a predictor of classification accuracy. The models were trained and validated on a database of 197 hip OA patients, and externally validated on 52 patients. The model accuracy was evaluated using exact class accuracy (ECA), one-neighbor class accuracy (ONCA), and balanced accuracy. RESULTS: The deep learning models produced a comparable accuracy of approximately 0.65 (ECA) and 0.95 (ONCA) in the classification and regression settings. The model uncertainty was significantly larger in cases with large classification errors ( P < 6 e - 3 ). CONCLUSIONS: In this study, an automatic approach for grading hip OA severity from CT images was developed. The models have shown comparable performance with high ONCA, which facilitates automated grading in large-scale CT databases and indicates the potential for further disease progression analysis. Classification accuracy was correlated with the model uncertainty, which would allow for the prediction of classification errors. The code will be made publicly available at https://github.com/NAIST-ICB/HipOA-Grading .

Electroacupuncture promotes macrophage/microglial M2 polarization and suppresses inflammatory pain through AMPK.

Inflammatory pain, the most prevalent disease globally, remains challenging to manage. Electroacupuncture emerges as an effective therapy, yet its underlying mechanisms are not fully understood. This study investigates whether adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)-regulated silent information regulator 1 (SIRT1) contributes to electroacupuncture's antinociceptive effects by modulating macrophage/microglial polarization in the spinal dorsal horn of a mouse model of inflammatory pain. In this study, mice, introduced to inflammatory pain through subcutaneous injections of complete freund's adjuvant (CFA) in the plantar area, underwent electroacupuncture therapy every alternate day for 30-min sessions. The assessment of mechanical allodynia and thermal hyperalgesia in these subjects was carried out using paw withdrawal frequency and paw withdrawal latency measurements, respectively. Western blot analysis measured levels of AMPK, phosphorylation-adenosine 5'-monophosphate (AMP)-activated protein kinase, SIRT1, inducible nitric oxide synthase, cluster of differentiation 86, arginase 1, and interleukin 10. In contrast to the group treated solely with CFA, the cohort receiving both CFA and electroacupuncture demonstrated notable decreases in both thermal hyperalgesia and mechanical allodynia. This was accompanied by a marked enhancement in AMPK phosphorylation levels. AMPK knockdown reversed electroacupuncture's analgesic effects and reduced M2 macrophage/microglial polarization enhancement. Additionally, AMPK knockdown significantly weakened electroacupuncture-induced SIRT1 upregulation, and EX-527 injection attenuated electroacupuncture's facilitation of M2 macrophage/microglial polarization without affecting AMPK phosphorylation levels. Furthermore, combining electroacupuncture with SRT1720 enhanced the analgesic effect of SRT1720. Our findings suggest that AMPK regulation of SIRT1 plays a critical role in electroacupuncture's antinociceptive effect through the promotion of M2 macrophage/microglial polarization.

Computational Exploration of 1,2-Carboamine Carbonylation Catalyzed by Nickel.

Nickel-catalyzed carbonylation of alkenes is a stereoselective and regioselective method for the synthesis of amide compounds. Theoretical predictions with density functional theory calculations revealed the mechanism and origin of stereoselectivity and regioselectivity for the nickel-catalyzed carbonylation of norbornene. The carbonylation reaction proceeds through oxidative addition, migration insertion of alkenes, and subsequent reduction elimination to afford cis-carbonylation product. The C-N bond activation of amides is unfavorable because the oxidative addition ability of the C-C bond is stronger than that of the C-N bond. The determining step of stereoselectivity is the migratory insertion of the strained olefin. The structural analysis shows that steroselectivity is controlled by the steric hindrance of methyl groups to olefins and substituents to IMes in ligands.

Qualitative and Quantitative Analytical Techniques of Nucleic Acid Modification Based on Mass Spectrometry for Biomarker Discovery.

Nucleic acid modifications play important roles in biological activities and disease occurrences, and have been considered as cancer biomarkers. Due to the relatively low amount of nucleic acid modifications in biological samples, it is necessary to develop sensitive and reliable qualitative and quantitative methods to reveal the content of any modifications. In this review, the key processes affecting the qualitative and quantitative analyses are discussed, such as sample digestion, nucleoside extraction, chemical labeling, chromatographic separation, mass spectrometry detection, and data processing. The improvement of the detection sensitivity and specificity of analytical methods based on mass spectrometry makes it possible to study low-abundance modifications and their biological functions. Some typical nucleic acid modifications and their potential as biomarkers are displayed, and efforts to improve diagnostic accuracy are discussed. Future perspectives are raised for this research field.

Impact of deep muscle invasion on nodal status and survival in patients with pT2 esophageal squamous cancer.

BACKGROUND: Whether T2 esophageal squamous cell carcinoma should be subclassified remains controversial. We aimed to investigate the impact of the depth of muscularis propria invasion on nodal status and survival outcomes. METHODS: We identified patients with pT2 esophageal squamous cell carcinoma who underwent primary surgery from January 2009 to June 2017. Clinical data were extracted from prospectively maintained databases. Tumor muscularis propria invasion was stratified into superficial or deep. Binary logistic regression was used to determine risk factors for lymph node metastases. The impact of the depth of muscularis propria invasion on survival was investigated using Kaplan‒Meier analysis and a Cox proportional hazard regression model. RESULTS: A total of 750 patients from three institutes were investigated. The depth of muscularis propria invasion (odds ratio [OR]: 3.95, 95% confidence interval [CI]: 2.46-6.35; p < 0.001) was correlated with lymph node metastases using logistic regression. T substage (hazard ratio [HR]: 1.37, 95% CI: 1.05-1.79; p < 0.001) and N status (HR: 1.51, 95% CI: 1.05-2.17; p < 0.001) were independent risk factors in multivariate Cox regression analysis. The deep muscle invasion was associated with worse overall survival (HR: 1.52, 95% CI: 1.19-1.94; p = 0.001) than superficial, specifically in T2N0 patients (HR: 1.38, 95% CI: 1.08-1.94; p = 0.035). CONCLUSIONS: We found that deep muscle invasion was associated with significantly worse outcomes and recommended the substaging of pT2 esophageal squamous cell carcinoma in routine pathological examination.

Effect of electroacupuncture on ventricular structure and function in rats with myocardial ischemia-reperfusion injury. / ç”µé’ˆå¯¹å¿ƒè‚Œç¼ºè¡€å†çŒæ³¨æŸä¼¤å¤§é¼ å¿ƒå®¤ç»“æž„å’ŒåŠŸèƒ½çš„å½±å“.

OBJECTIVES: To observe the effect of electroacupuncture (EA) on changes of ventricular structure and function in rats with myocardial ischemia-reperfusion injury (MIRI), so as to explore its potential mechanisms underlying improvement of ventricular remodeling after MIRI. METHODS: Forty male SD rats were randomly divided into 4 groups：sham operation group, model group, EA group and medication (sacubactril valsartan, LCZ696) group, with 10 rats in each group. The MIRI model was established by ligation of the left anterior descending coronary artery and reperfusion. EA (2 Hz/100 Hz, 2 mA) was applied to bilateral "Neiguan" (PC6) for 20 min, once every other day for 21 d. Rats of the medication group received gavage of LCZ696 (60 mg·kg-1·d-1). After the intervention, echocardiography was used to detect the ejection fraction (EF) and fractional shortening (FS) of the left ventricle, and the contents of serum tumor necrosis factor-α(TNF-α), vascular cell adhesion molecule-1(VCAM-1) and intercellular cell adhesion molecule-1(ICAM-1) were assayed by enzyme-linked immunosorbent assay. The pathological changes of myocardial tissue were observed after HE staining. The Masson staining was used to evaluate the myocardial collagen deposition and myocardial fibrosis. The mRNA expression levels of collagen Ⅰ and Ⅲ and connective tissue growth factor (CTGF) in the myocardial tissue were detected by quantitative real-time PCR, and the expression levels of IL-1ß and IL-18 were detected by Western blot. RESULTS: In contrast to the sham operation group, the EF and FS levels of the left ventricle were ob-viously decreased (P<0.001), while the contents of serum TNF-α, VCAM-1 and ICAM-1, the proportion of myocardial fibrosis area, the mRNA expression levels of myocardial collagen Ⅰ, collagen Ⅲ and CTGF, the expression levels of IL-1ß and IL-18 were significantly increased (P<0.001, P<0.000 1, P<0.05, P<0.01) in the model group. Compared with the model group, the EF and FS levels were remarkably increased (P<0.01), whereas the contents of serum TNF-α, VCAM-1 and ICAM-1, the proportion of myocardial fibrosis area, the mRNA expression levels of myocardial collagen Ⅰ, collagen Ⅲ and CTGF, and the expression levels of IL-1ß and IL-18 were significantly down-regulated (P<0.001, P<0.01, P<0.05) in both the medication and EA groups. No significant differences were found between the EA and medication groups in all the indexes mentioned above. CONCLUSIONS: EA can improve the left-ventricular fibrosis and function, delay or reverse ventricular remodeling in MIRI rats, which may be related to its functions in down-regulating myocardial inflammatory response and mRNA expression levels of myocardial collagen Ⅰ, collagen Ⅲ and CTGF.

Pseudomonas cucumis sp. nov., isolated from the rhizosphere of crop plants.

Two bacterial strains, FP1935T and FP1962, were isolated from the rhizosphere soil of cucumber and Chieh-qua plants, respectively, in Jilin Province, PR China. These strains were Gram-stain-negative, aerobic, rod-shaped and motile with one or two polar flagella. Analysis of the 16S rRNA gene sequences revealed that they represented members of the genus Pseudomonas, with the highest similarity to Pseudomonas silesiensis A3T (99.45 %), Pseudomonas frederiksbergensis JAJ28T (99.45 %), Pseudomonas mandelii NBRC 103147T (99.38 %), Pseudomonas piscium P50T (99.27 %) and Pseudomonas meliae CFBP 3225T (99.18 %). The DNA G+C contents of FP1935T and FP1962 were 58.99 mol% and 58.98 mol%, respectively. The results of in silico genome-based analyses indicated that these strains were distinct from other species in the genus Pseudomonas, as the average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values were below the recommended thresholds of 95 % (ANI) and 70 % (dDDH) for prokaryotic species delineation, with no values exceeding 94.1 and 55.8 %, respectively, compared with any other related species. The results of phenotypic and chemotaxonomic tests confirmed their differentiation from their closest relatives. The fatty acid profiles of both strains mainly consisted of summed feature 3 (C16 : 1ω6c and/or C16 : 1ω7c), summed feature 8 (C18 : 1ω7c and/or C18 : 1ω6c), C12 : 0 and C16 : 0. The predominant respiratory quinone was Q-9. Polar lipids include phosphatidylethanolamine, unidentified aminophospholipids, unidentified lipids and an unidentified phospholipid. On the basis of these phenotypic and genotypic results, we propose the name Pseudomonas cucumis sp. nov. for these novel strains. The type strain is FP1935T (=ACCC 62445T=JCM 35690T).

Unraveling intratumoral complexity in metastatic dermatofibrosarcoma protuberans through single-cell RNA sequencing analysis.

Dermatofibrosarcoma protuberans (DFSP) stands as a rare and locally aggressive soft tissue tumor, characterized by intricated molecular alterations. The imperative to unravel the complexities of intratumor heterogeneity underscores effective clinical management. Herein, we harnessed single-cell RNA sequencing (scRNA-seq) to conduct a comprehensive analysis encompassing samples from primary sites, satellite foci, and lymph node metastases. Rigorous preprocessing of raw scRNA-seq data ensued, and employing t-distributed stochastic neighbor embedding (tSNE) analysis, we unveiled seven major cell populations and fifteen distinct subpopulations. Malignant cell subpopulations were delineated using infercnv for copy number variation calculations. Functional and metabolic variations of diverse malignant cell populations across samples were deciphered utilizing GSVA and the scMetabolism R packages. Additionally, the exploration of differentiation trajectories within diverse fibroblast subpopulations was orchestrated through pseudotime trajectory analyses employing CytoTRACE and Monocle2, and further bolstered by GO analyses to elucidate the functional disparities across distinct differentiation states. In parallel, we segmented the cellular components of the immune microenvironment and verified the presence of SPP1+ macrophage, which constituted the major constituent in lymph node metastases. Remarkably, the CellChat facilitated a comprehensive intercellular communication analysis. This study culminates in an all-encompassing single-cell transcriptome atlas, propounding novel insights into the multifaceted nature of intratumor heterogeneity and fundamental molecular mechanisms propelling metastatic DFSP.

Deltonin enhances gastric carcinoma cell apoptosis and chemosensitivity to cisplatin via inhibiting PI3K/AKT/mTOR and MAPK signaling.

BACKGROUND: As an active ingredient derived from Dioscorea zingiberensis C.H. Wright, deltonin has been reported to show anti-cancer effects in a variety of malignancies. AIM: To investigate the role and mechanism of action of deltonin in promoting gastric carcinoma (GC) cell apoptosis and chemosensitivity to cisplatin. METHODS: The GC cell lines AGS, HGC-27, and MKN-45 were treated with deltonin and then subjected to flow cytometry and 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltetrazolium bromide assays for cell apoptosis and viability determination. Western blot analysis was conducted to examine alterations in the expression of apoptosis-related proteins (Bax, Bid, Bad, and Fas), DNA repair-associated proteins (Rad51 and MDM2), and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/AKT/mTOR) and p38-mitogen-activated protein kinase (MAPK) axis proteins. Additionally, the influence of deltonin on GC cell chemosensitivity to cisplatin was evaluated both in vitro and in vivo. RESULTS: Deltonin treatment weakened viability, enhanced apoptosis, and dampened DNA repair in GC cell lines in a dose-dependent pattern. Furthermore, deltonin mitigated PI3K, AKT, mTOR, and p38-MAPK phosphorylation. HS-173, an inhibitor of PI3K, attenuated GC cell viability and abolished deltonin inhibition of GC cell viability and PI3K/AKT/mTOR and p38-MAPK pathway activation. Deltonin also promoted the chemosensitivity of GC cells to cisplatin via repressing GC cell proliferation and growth and accelerating apoptosis. CONCLUSION: Deltonin can boost the chemosensitivity of GC cells to cisplatin via inactivating p38-MAPK and PI3K/AKT/mTOR signaling.

Higher cadmium exposure was associated with sex-specific thyroid dysfunction: Consistent evidence from two independent cross-sectional studies based on urinary and blood cadmium measurements.

Population-based studies on the association between cadmium (Cd) exposure and thyroid function are limited and have shown conflicting results. Two independent cross-sectional studies using different Cd biomarkers were carried out in six rural areas with different soil Cd levels in China. Thyroid dysfunction was defined based on levels of thyroid stimulating hormone (TSH) and free thyroxine (FT4). Both multivariable linear regression, multiple logistic regression and restrictive cubic splines models were used to estimate the association between Cd and thyroid dysfunction. For both of the two independent studies, higher Cd levels were observed to be associated with lower TSH levels and higher risk of thyroid dysfunction. The negative relationship between urinary Cd and TSH was found in both total participants (ß = -0.072, p = 0.008) and males (ß = -0.119, p = 0.020) but not in females, however, the negative relationship between blood Cd and TSH was only found in females (ß = -0.104, p = 0.024). Higher urinary Cd (> 2.52 µg/g creatinine) was associated with higher risk of thyroid dysfunction, while higher blood Cd was associated with higher risk of hyperthyroidism status. The adjusted Odds Ratio (OR) for the risk of hyperthyroidism status was 3.48 (95%CI:1.36-8.92) and 6.94 (95%CI:1.23-39.31) times higher with every natural log unit higher in blood Cd in total participants and males, respectively. Results from the two independent cross-sectional studies consistently suggested that higher Cd levels were associated with sex-specific thyroid dysfunction.

Development of a highly sensitive immunoassay based on pentameric nanobodies for carcinoembryonic antigen detection.

BACKGROUND: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM-5) is a well-characterized biomarker for the clinical diagnosis of various cancers. Nanobodies, considered the smallest antibody fragments with intact antigen-binding capacity, have gained significant attention in disease diagnosis and therapy. Due to their peculiar properties, nanobodies have become promising alternative diagnostic reagents in immunoassay. However, nanobodies-based immunoassay is still hindered by small molecular size and low antigen capture efficacy. Therefore, there is a pressing need to develop novel nanobody-based immunoassays with superior performance. RESULTS: A novel pentameric nanobodies-based immunoassay (PNIA) was developed with enhanced sensitivity and specificity for CEACAM-5 detection. The binding epitopes of three anti-CEACAM-5 nanobodies (Nb1, Nb2 and Nb3) were analyzed. To enhance the capture and detection efficacy of CEACAM-5 in the immunoassay, we engineered bispecific nanobodies (Nb1-Nb2-rFc) as the capture antibody, and developed the FITC-labeled pentameric nanobodies (Nb3-VT1B) as the detection antibody. The binding affinities of Nb1-Nb2-rFc (1.746 × 10-10) and Nb3-VT1B (1.279 × 10-11) were significantly higher than those of unmodified nanobodies (Nb1-rFc, 4.063 × 10-9; Nb2-rFc, 2.136 × 10-8; Nb3, 3.357 × 10-9). The PNIA showed a linear range of 0.625-160 ng mL-1 with a correlation coefficient R2 of 0.9985, and a limit of detection of 0.52 ng mL-1, which was 24-fold lower than the immunoassay using monomeric nanobody. The PNIA was validated with the spiked human serum. The average recoveries ranged from 91.8% to 102% and the coefficients of variation ranged from 0.026% to 0.082%. SIGNIFICANCE AND NOVELTY: The advantages of nanobodies offer a promising alternative to conventional antibodies in disease diagnosis. The novel PNIA demonstrated superior sensitivity and high specificity for the detection of CEACAM-5 antigen. This bispecific or multivalent nanobody design will provide some new insights into the design of immunoassays for clinical diagnosis.

[Lidong needling therapy combined with functional exercise in treatment of upper limb lymphedema after breast cancer surgery: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy of lidong needling therapy (acupuncture technique combined with therapeutic movement of the body) on upper limb lymphedema after breast cancer surgery in combination with functional exercise. METHODS: A total of 73 patients with postoperative lymphedema of breast cancer in the upper limbs were randomized into an observation group (36 cases) and a control group (37 cases). The routine nursing care and functional exercise were given in the control group, twice a day, for about 10-15 min each time, lasting 8 weeks. On the basis of the treatment as the control group, lidong needling therapy was applied to the acupionts on the affected upper limb, i.e. Jianyu (LI 15), Waiguan (TE 5), Hegu (LI 4) and ashi points (the most obvious swelling sites), as well as to bilateral Yinlingquan (SP 9) and Zusanli (ST 36), etc. The needles were retained for 30 min. While the needles retained, the patients were asked to move the affected shoulder to 90° by the sagittal anteflexion and keep it elevated. Simultaneously, the hand on the affected side was clenched and opened slowly and coordinately. Lidong needling therapy was delivered once every two days, three times weekly for 8 weeks. Before and after treatment, the difference of the circumference between the affected and healthy limbs, the score of visual analogue scale (VAS) for swelling and the score of disability of arm, shoulder and hand (DASH) were compared in the patients of the two groups. The clinical efficacy was evaluated. RESULTS: After 2, 4, 6 and 8 weeks of treatment, except for the circumference of the area 10 cm below the cubitel crease in the control group, the differences in the circumferences of the rest parts between the affected and healthy limbs were reduced in comparison with those before treatment in the two groups (P<0.01, P<0.05). After 6 weeks of treatment, in the observation group, for the circumference at the level of hand between the thumb and the index finger and that of the wrist, the differences between the affected and healthy limbs was smaller compared with those in the control group (P<0.05). After 8 weeks of treatment, except for the areas 5 cm below and above the cubitel crease, the differences of circumferences between the affected and healthy limbs in the observation group were smaller than those in the control group in the rest parts (P<0.01, P<0.05). After 8 weeks of treatment, the swelling VAS scores were reduced when compared with those before treatment in the two groups (P<0.05), and the score in the observation group was lower than that in the control group (P<0.01). After 4 and 8 weeks of treatment, DASH scores were reduced in comparison with those before treatment in the two groups (P<0.01). The total effective rate of the observation group was 83.3% (30/36), which was higher than that of the control group (35.1%, 13/37, P<0.01). CONCLUSION: Lidong needling therapy combined with the functional exercise obtains the satisfactory clinical effect on the upper limb lymphedema after breast cancer surgery. This treatment effectively relieves swelling and improves the upper limb function.