Targeting the CDK7-MDK axis to suppresses irinotecan resistance in colorectal cancer.

AIMS: Colorectal cancer (CRC) remains a major global health issue, with metastatic cases presenting poor prognosis despite advances in chemotherapy and targeted therapy. Irinotecan, a key drug for advanced CRC treatment, faces challenges owing to the development of resistance. This study aimed to understand the mechanisms underlying irinotecan resistance in colorectal cancer. MAIN METHODS: We created a cell line resistant to irinotecan using HT29 cells. These resistant cells were utilized to investigate the role of the CDK7-MDK axis. We employed bulk RNA sequencing, conducted in vivo experiments with mice, and analyzed patient tissues to examine the effects of the CDK7-MDK axis on the cellular response to irinotecan. KEY FINDINGS: Our findings revealed that HT29 cells resistant to irinotecan, a crucial colorectal cancer medication, exhibited significant phenotypic and molecular alterations compared to their parental counterparts, including elevated stem cell characteristics and increased levels of cytokines and drug resistance proteins. Notably, CDK7 expression was substantially higher in these resistant cells, and targeting CDK7 effectively decreased their survival and tumor growth, enhancing irinotecan sensitivity. RNA-seq analysis indicated that suppression of CDK7 in irinotecan-resistant HT29 cells significantly reduced Midkine (MDK) expression. Decreased CDK7 and MDK levels, achieved through siRNA and the CDK7 inhibitor THZ1, enhanced the sensitivity of resistant HT29 cells to irinotecan. SIGNIFICANCE: Our study sheds light on how CDK7 and MDK influence irinotecan resistance in colorectal and highlights the potential of MDK-targeted therapies. We hypothesized that irinotecan sensitivity and overall treatment efficacy would improve by inhibiting MDK. This finding encourages a careful yet proactive investigation of MDK as a therapeutic target to enhance outcomes in colorectal cancer patients.

A thorough investigation into the adsorption behavior of sophorolipid-modified fly ash towards compound pollution of lead and tetracycline.

Heavy metal ions and antibiotics were simultaneously detected in authentic water systems. This research, for the first time, employed synthesized sophorolipid-modified fly ash(SFA) to eliminate tetracycline(TC) and lead(Pb2+) from wastewater. Various characterization techniques, including SEM-EDS, FTIR, XPS, BET, and Zeta, were employed to investigate the properties of the SFA. The results showed that the sophorolipid modification significantly improved the fly ash's adsorption capacities for the target pollutants. The static adsorption experiments elucidated the adsorption behaviors of SFA towards TC and Pb2+ in single and binary systems, highlighting the effects of different Environmental factors on the adsorption behavior in both types of systems. In single systems, SFA exhibited a maximum adsorption capacity of 128.96 mg/g for Pb2+ and 55.57 mg/g for TC. The adsorption of Pb2+ and TC followed pseudo-second-order kinetics and Freundlich isotherm models. The adsorption reactions are endothermic and occur spontaneously. SFA demonstrates varying adsorption mechanisms for two different types of pollutants. In the case of Pb2+, the primary mechanisms include ion exchange, electrostatic interaction, cation-π interaction, and complexation, while TC primarily engages in hydrogen bonding, π-π interaction, and complexation. The interaction between Pb2+ and TC has been shown to improve adsorption efficiency at low concentrations. Additionally, adsorption-desorption experiments confirm the reliable cycling performance of modified fly ash, highlighting its potential as a cost-effective and efficient adsorbent for antibiotics and heavy metals.

Material flow analysis of heavy metals in large-scale cattle farms and ecological risk assessment of cattle manure application to fields.

This study bridges the knowledge gap pertaining to the pathways of heavy metal accumulation and migration within the industrial chain of large-scale cattle farms. Two such farms in Shaanxi serve as a basis for our exploration into Zn, Cu, Cr, Pb, As, and Cd dynamics. Employing material flow analysis complemented by predictive models, we evaluate the potential ecological risks of arable soil from heavy metal influx via manure application. Our findings indicate that Zn and Cu predominate the heavy metal export from these operations, composing up to 60.00%-95.67% of their total content. Predictive models based on 2021 data reveal a potential increase in Cd soil concentration by 0.08 mg/kg by 2035, insinuating a reduced safe usage period for cattle manure at less than 50 years. Conversely, projections from 2022 data point towards a gradual Cu rise in soil, reaching risk threshold levels after 126 years. These outcomes inform limitations in cattle manure utilisation strategies, underscoring Cu and Cd content as key barriers. The study underscores the criticality of continuous heavy metal surveillance within farm by products to ensure environmental protection and sustainable agricultural practices.

Evaluating Recurrence Risk in Patients Undergoing Breast-conserving Surgery Using E-cadherin Staining as a Biomarker.

BACKGROUND/AIM: Following the National Comprehensive Cancer Network guidelines, radiotherapy is administered after breast-conserving surgery (BCS) in patients with more than four positive lymph nodes. Four positive lymph nodes are typically considered an indicator to assess disease spread and patient prognosis. However, the subjective counting of positive axillary lymph nodes underscores the need for biomarkers to improve diagnostic precision and reduce the risk of unnecessary treatments. Loss of E-cadherin expression is associated with cancer metastasis, but its potential as a predictive marker for cancer treatment remains uncertain. This study aimed to investigate the validity of E-cadherin as a reference for adjuvant radiotherapy in breast cancer patients with positive lymph nodes post-mastectomy. MATERIALS AND METHODS: Immunohistochemistry was performed on 60 clinical tissue specimens to assess these implications. RESULTS: Although no significant result was found in a single E-cadherin subgroup (low, medium, and high subgroups according to the X-tile algorithm), the proposed multivariate model, including the E-cadherin category, breast cancer subtype, and tumor size, yielded satisfactory recurrence risk estimation results for patients undergoing BCS. Patients with a low E-cadherin category, triple-negative breast cancers, and tumor size over 5 cm could have an increased risk of recurrence. CONCLUSION: Our study proposed a multivariate model that serves as a candidate prognostic factor for recurrence-free survival in patients undergoing BCS and radiotherapy. Utilizing this model for patient stratification in high-risk diseases and as a standard for assessing postoperative intensified therapy can potentially improve patient outcomes.

A Water-Based Biocoating to Increase the Infection Resistance and Osteoconductivity of Titanium Surfaces.

As the population ages, the number of patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) continues to increase. Infections after primary arthroplasty are rare but have high rates of morbidity and mortality, as well as enormous financial implications for healthcare systems. Numerous methods including the use of superhydrophobic coatings, the incorporation of antibacterial agents, and the application of topographical treatments have been developed to reduce bacterial attachment to medical devices. However, most of these methods require complex manufacturing processes. Thus, the main purpose of this study was to apply biocoatings to titanium (Ti) surfaces to increase their infection resistance and osteoconductivity via simple processes, without organic reagents. We modified titanium surfaces with a combination of aminomalononitrile (AMN) and an antibiotic-loaded mesoporous bioactive glass (MBG) and evaluated both the antibacterial effects of the coating layer and its effect on osteoblast proliferation and differentiation. The properties of the modified surface, such as the hydrophilicity, roughness, and surface morphology, were characterized via contact angle measurements, atomic force microscopy, and scanning electron microscopy. The cell proliferation reagent WST-1 assay and the alkaline phosphatase (ALP) assay were used to determine the degrees of adhesion and differentiation, respectively, of the MG-63 osteoblast-like cells on the surface. Antimicrobial activity was evaluated by examining the survival rate and inhibition zone of Escherichia coli (E. coli). The AMN coating layer reduced the water contact angle (WCA) of the titanium surface from 87° ± 2.5° to 53° ± 2.3° and this change was retained even after immersion in deionized water for five weeks, demonstrating the stability of the AMN coating. Compared with nontreated titanium and polydopamine (PDA) coating layers, the AMN surface coating increased MG-63 cell attachment, spreading, and early ALP expression; reduced E. coli adhesion; and increased the percentage of dead bacteria. In addition, the AMN coating served as an adhesion layer for the subsequent deposition of MBG-containing antibiotic nanoparticles. The synergistic effects of the AMN layer and antibiotics released from the MBG resulted in an obvious E. coli inhibition zone that was not observed in the nontreated titanium group.

Cadmium exposure causes transcriptomic dysregulation in adipose tissue and associated shifts in serum metabolites.

Cadmium (Cd) is a toxic heavy metal found in natural and industrial environments. Exposure to Cd can lead to various metabolic disturbances, notably disrupting glucose and lipid homeostasis. Despite this recognition, the direct impact of Cd exposure on lipid metabolism within adipose tissue, and the mechanisms underlying these effects, have not been fully elucidated. In this study, we found that Cd accumulates in adipose tissues of mice subjected to Cd exposure. Intriguingly, Cd exposure in itself did not induce significant alterations in the adipose tissue under normal conditions. However, when subjected to cold stimulation, several notable changes were observed in the mice exposed to Cd, including a reduction in the drop of body temperature, a decrease in the size of inguinal white adipose tissue (WAT), and an increase in the expression of thermogenic genes UCP1 and PRDM16. These results indicate that Cd exposure might enhance the responsiveness of adipose tissue to external stimuli and increase the energy expenditure of the tissue. RNA-seq analysis further revealed that Cd exposure altered gene expression profiles, particularly affecting peroxisome proliferator-activated receptor (PPAR)-mediated metabolic pathways, promoting metabolic remodeling in adipose tissue and resulting in the depletion of lipids stored in adipose tissue for energy. Non-targeted metabolomic analysis of mouse serum showed that Cd exposure significantly disrupted metabolites and significantly increased serum fatty acid and triglyceride levels. Correspondingly, population-level data confirmed an association between Cd exposure and elevated levels of serum total cholesterol, total triglycerides, and low-density lipoprotein cholesterol. In summary, we provide substantial evidence of the molecular events induced by Cd that are relevant to the regulation of lipid metabolism in adipose tissue. Our findings suggest that the toxic effects of Cd can impact adipocyte functionality, positioning adipose tissue as a critical target for metabolic diseases resulting from Cd exposure.

Multiplane differential saturated excitation microscopy using varifocal lenses.

Saturated excitation microscopy, which collects nonlinear fluorescence signals generated by saturation, has been proposed to improve three-dimensional spatial resolution. Differential saturated excitation (dSAX) microscopy can further improve the detection efficiency of a nonlinear fluorescence signal. By comparing signals obtained at different saturation levels, high spatial resolution can be achieved in a simple and efficient manner. High-resolution multiplane microscopy is perquisite for volumetric imaging of thick samples. To the best of our knowledge, no reports of multiplane dSAX have been made. Our aim is to obtain multiplane high-resolution optically sectioned images by adapting differential saturated excitation in confocal laser scanning fluorescence microscopy. To perform multiplane dSAX microscopy, a variable focus lens is employed in a telecentric design to achieve focus tunability with constant magnification and contrast throughout the axial scanning range. Multiplane fluorescence imaging of two different types of pollen grains shows improved resolution and contrast. Our system's imaging performance is evaluated using standard targets, and the results are compared with standard confocal microscopy. Using a simple and efficient method, we demonstrate multiplane high-resolution fluorescence imaging. We anticipate that high-spatial resolution combined with high-speed focus tunability with invariant contrast and magnification will be useful in performing 3D imaging of thick biological samples.

Enhancing the carbon content of coal gangue for composting through sludge amendment: A feasibility study.

Cocomposting coal gangue and sludge eliminates the challenge of utilizing coal gangue. However, there is limited understanding about the feasibility of cocomposting sludge and coal gangue, as well as the composting indicators, functional microorganisms, and safety risks involved. Therefore, this study evaluated the feasibility of enhancing carbon composting in coal gangue by incorporating sludge along with sawdust as a conditioner. Three laboratory-scale reactors were designed and labeled as T1 (20 % coal gangue, 60 % sludge, and 20 % sawdust), T2 (40 % coal gangue, 40 % sludge, and 20 % sawdust), and T3 (60 % coal gangue, 20 % sludge, and 20 % sawdust). Seed germination and plant growth assessments were conducted to ensure compost stability and assess phytotoxicity to cabbage (Brassica rapa chinensis L.) in terms of growth and biomass. The results indicated that the temperature, pH, EC and ammonia nitrogen of all three reactor conditions met the requirements for product decomposition. Composting was successfully achieved when the sludge proportion was 20 % (T3). However, when the sludge proportion was markedly high (T1), the harmlessness of the compost was reduced. The germination indices of T1, T2, and T3 reached 95 %, 122 %, and 119 % at maturity, respectively. This confirmed that the harmless cycle, which involved promoting condensation and aromatization, enhancing decay, and reducing composting time, was shorter in T2 and T3 than in T1. Coal gangue can also serve as a beneficial habitat for microorganisms, promoting an increase in their population and activity. Potting experiments in sandy soil revealed that the mechanism of action of compost products in soil included not only the enhancement of soil nutrients but also the improvement of soil texture. The results of this study suggest that using coal gangue as a raw material for composting is an efficient and environmentally friendly approach for producing organic fertilizers.

Reliability of the michigan state university (msu) classification of lumbar disc herniation / Confiabilidade da universidade do estado de michigan (msu) classificação da herniação de disco lombar

ABSTRACT Objective: The Michigan State University (MSU) classification of lumbar disc herniation (LDH) is periodically used by various authors to classify disc herniation. We assessed the reliability of this classification system among orthopedic residents at our institute. Methods: Fifty T2 axial-cut magnetic resonance images (MRI) corresponding to the level of maximal disc herniation from patients diagnosed with a single LDH were selected and distributed to six orthopedic residents. All six residents gave a specific rating for each image based on the MSU classification; in addition, three residents gave ratings on two different occasions. The degree of agreement among residents was analyzed by calculating inter-observer and intra-observer reliability using the Kappa statistic. Results: The inter-observer reliability among the six residents calculated as the Fleiss' Kappa was 0.422, which indicates moderate reliability. The intra-observer reliability of three selected residents calculated by Cohen's Kappa was 0.750, 0.772, and 0.859, which indicates substantial to almost perfect reliability. Variations in ratings were frequent in images portraying a broad-based disc herniation with spinal canal stenosis. Conclusion: Our findings demonstrate moderate homogeneity of ratings given by residents; however, test-retest results proved the ratings to be consistent. Level of Evidence II, Diagnostic studies - investigating a diagnostic examination.

RESUMO Objetivo: A classificação da hérnia de disco lombar (LDH) da Michigan State University (MSU) é usada periodicamente por vários autores para classificar as hérnias discais. Pretendemos avaliar a confiabilidade deste sistema de classificação entre os residentes de ortopedia em nosso instituto. Métodos: Cinqüenta imagens de RM axial do corte T2 correspondendo ao nível de hérnia discal máxima de pacientes que foram diagnosticados com uma única LDH foram selecionadas e distribuídas para seis residentes ortopédicos. Todos os seis residentes deram uma classificação específica para cada imagem com base na classificação MSU; Além disso, três residentes deram notas em duas ocasiões diferentes. O grau de concordância entre os residentes foi analisado calculando-se a confiabilidade interobservador e intraobservador pela estatística Kappa. Resultados: Descobrimos que a confiabilidade interobservador entre seis residentes, calculando o Kappa de Fleiss, foi de 0,422; isso indica confiabilidade moderada. No entanto, a confiabilidade intra-observador de três residentes selecionados mostrou-se substancial (Kappa de Cohen = 0,750, 0,772 e 0,859 em três residentes, respectivamente). Variações na observação foram frequentes se houvesse hérnia discal ampla com estenose do canal vertebral. Conclusão: Nossos achados demonstram homogeneidade moderada das avaliações dadas pelos residentes; no entanto, teste-reteste provou que as classificações eram consistentes. Nível de Evidencia II, Estudos diagnósticos - investigação de um exame para diagnóstico.