ZEB family is a prognostic biomarker and correlates with anoikis and immune infiltration in kidney renal clear cell carcinoma.

BACKGROUND: Zinc finger E-box binding homEeobox 1 (ZEB1) and ZEB2 are two anoikis-related transcription factors. The mRNA expressions of these two genes are significantly increased in kidney renal clear cell carcinoma (KIRC), which are associated with poor survival. Meanwhile, the mechanisms and clinical significance of ZEB1 and ZEB2 upregulation in KIRC remain unknown. METHODS: Through the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, expression profiles, prognostic value and receiver operating characteristic curves (ROCs) of ZEB1 and ZEB2 were evaluated. The correlations of ZEB1 and ZEB2 with anoikis were further assessed in TCGA-KIRC database. Next, miRTarBase, miRDB, and TargetScan were used to predict microRNAs targeting ZEB1 and ZEB2, and TCGA-KIRC database was utilized to discern differences in microRNAs and establish the association between microRNAs and ZEBs. TCGA, TIMER, TISIDB, and TISCH were used to analyze tumor immune infiltration. RESULTS: It was found that ZEB1 and ZEB2 expression were related with histologic grade in KIRC patient. Kaplan-Meier survival analyses showed that KIRC patients with low ZEB1 or ZEB2 levels had a significantly lower survival rate. Meanwhile, ZEB1 and ZEB2 are closely related to anoikis and are regulated by microRNAs. We constructed a risk model using univariate Cox and LASSO regression analyses to identify two microRNAs (hsa-miR-130b-3p and hsa-miR-138-5p). Furthermore, ZEB1 and ZEB2 regulate immune cell invasion in KIRC tumor microenvironments. CONCLUSIONS: Anoikis, cytotoxic immune cell infiltration, and patient survival outcomes were correlated with ZEB1 and ZEB2 mRNA upregulation in KIRC. ZEB1 and ZEB2 are regulated by microRNAs.

Learning pathways composed of core subjects with features of reducing cognitive load have better learning outcomes.

BACKGROUND: Changing the course duration or timing of subjects in learning pathways would influence medical students' learning outcomes. Curriculum designers need to consider the strategy of reducing cognitive load and evaluate it continuously. Our institution underwent gradual curricular changes characterized by reducing cognitive load since 2000. Therefore, we wanted to explore the impact of this strategy on our previous cohorts. METHODS: This cohort study explored learning pathways across academic years of more than a decade since 2000. Eight hundred eighty-two medical students between 2006 to 2012 were included eventually. Learning outcomes included an average and individual scores of subjects in different stages. Core subjects were identified as those where changes in duration or timing would influence learning outcomes and constitute different learning pathways. We examined whether the promising learning pathway defined as the pathway with the most features of reducing cognitive load has higher learning outcomes than other learning pathways in the exploring dataset. The relationship between features and learning outcomes was validated by learning pathways selected in the remaining dataset. RESULTS: We found nine core subjects, constituting four different learning pathways. Two features of extended course duration and increased proximity between core subjects of basic science and clinical medicine were identified in the promising learning pathway 2012, which also had the highest learning outcomes. Other pathways had some of the features, and pathway 2006 without such features had the lowest learning outcomes. The relationship between higher learning outcomes and cognitive load-reducing features was validated by comparing learning outcomes in two pathways with and without similar features of the promising learning pathway. CONCLUSION: An approach to finding a promising learning pathway facilitating students' learning outcomes was validated. Curricular designers may implement similar design to explore the promising learning pathway while considering potential confounding factors, including students, medical educators, and learning design of the course.

Exploring the optimal lower blood pressure boundary during endovascular thrombectomy in patients with large vessel occlusion.

BACKGROUND: Current guidelines advocate for maintaining BP level below 180/105 mmHg during EVT, determining the safe lower boundary remains primarily consensus-driven by experts. This study aims to delve into the correlation between various targets of lower boundary for systolic and diastolic BP (SBP and DBP) during EVT and 3-month functional outcomes. METHODS: A cohort study was conducted across two EVT-capable centers, enrolling patients with large artery occlusion undergoing EVT within 8 h of stroke onset. Mean BP values during EVT were meticulously recorded, and logistic regression models were utilized to evaluate the correlation between outcomes and diverse lower boundary targets for SBP and DBP. Additionally, logistic regression models investigated the relationship between periprocedural BP variability and subsequent outcomes. RESULTS: Among the 201 patients included, having a SBP higher than 130 or 140 mmHg showed an independent association with increased good functional outcomes at 3 months (adjusted odds ratio, aOR 2.80, 95% Cis, 1.26-6.39 for 140 mmHg; aOR 2.34, 95% Cis, 1.03-5.56 for 130 mmHg). Additionally, an SBP exceeding 130 mmHg was correlated with decreased 3-month mortality (aOR, 0.24, 95% CI 0.07-0.74). No significant relationship was observed between DBP and functional outcomes. Patients with higher periprocedural SBP coefficient variance exhibited a decreased rate of good functional outcomes at 3 months (aOR, 0.42, 95% CI, 0.18-0.96). CONCLUSIONS: A SBP range above 130-140 mmHg could potentially serve as a safe lower boundary during EVT, while minimizing BP fluctuations may correlate with improved post-EVT functional outcomes.

Impact of unplanned second debridement, antibiotics and implant retention on long-term outcomes in knee exchange arthroplasty: Elevated risk of failure and reinfection.

Purpose: This study investigates the outcomes of two-stage exchange arthroplasty (EA) for periprosthetic joint infection (PJI) following initial or unplanned repeat debridement antibiotics, and implant retention (DAIR). Methods: We retrospectively reviewed cases of knee arthroplasty infection treated with two-stage EA after DAIR, spanning from January 1994 to December 2010. A total of 138 patients were included, comprising 112 with initial DAIR and 26 with an unplanned second DAIR. Data on demographics, comorbidities, infection characteristics and causative organisms were analyzed. The primary outcome was implant failure or reinfection, observed over a minimum follow-up of 10 years. Results: The overall success rate for two-stage EA was 87% (119/138 patients). Factors identified for treatment failure included reinfection with the same pathogen for unplanned second DAIR (hazard ratio [HR] = 3.41; 95% confidence interval [CI] = 1.35-4.38; p = 0.004), higher reinfection rates in patients undergoing EA after an unplanned second DAIR, especially with a prior history of PJI within 2 years (HR = 4.23; 95% CI = 2.39-5.31; p = 0.002), pre-first DAIR C-reactive protein (CRP) levels over 100 mg/dL (HR = 2.52; 95% CI = 1.98-3.42; p = 0.003) and recurrence with the same pathogen (HR = 2.35; 95% CI = 1.32-4.24; p = 0.007). Additional factors such as male gender (HR = 3.92; 95% CI = 1.21-5.25; p = 0.007) and osteoporosis (T score < -2.5; HR = 3.27; 95% CI = 1.23-5.28; p = 0.005) were identified as risk factors for implant failure in all EA cases. Conclusions: This study identifies key risk factors for worse knee EA outcomes following DAIR, including a pre-first DAIR CRP level over 100 mg/L, same pathogen recurrence, and PJI history within 2 years. It shows implant failure rates remain constant across EA cases, regardless of DAIR sequence, particularly with risk factors like male gender and severe osteoporosis (T score < -2.5). These results underscore the need for careful evaluation before an unplanned second DAIR, given its significant impact on EA success. Level of Evidence: Level III.

Early Identification of Sepsis-Induced Acute Kidney Injury by Using Monocyte Distribution Width, Red-Blood-Cell Distribution, and Neutrophil-to-Lymphocyte Ratio.

Sepsis-induced acute kidney injury (AKI) is a common complication in patients with severe illness and leads to increased risks of mortality and chronic kidney disease. We investigated the association between monocyte distribution width (MDW), red-blood-cell volume distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), sepsis-related organ-failure assessment (SOFA) score, mean arterial pressure (MAP), and other risk factors and sepsis-induced AKI in patients presenting to the emergency department (ED). This retrospective study, spanning 1 January 2020, to 30 November 2020, was conducted at a university-affiliated teaching hospital. Patients meeting the Sepsis-2 consensus criteria upon presentation to our ED were categorized into sepsis-induced AKI and non-AKI groups. Clinical parameters (i.e., initial SOFA score and MAP) and laboratory markers (i.e., MDW, RDW, and NLR) were measured upon ED admission. A logistic regression model was developed, with sepsis-induced AKI as the dependent variable and laboratory parameters as independent variables. Three multivariable logistic regression models were constructed. In Model 1, MDW, initial SOFA score, and MAP exhibited significant associations with sepsis-induced AKI (area under the curve [AUC]: 0.728, 95% confidence interval [CI]: 0.668-0.789). In Model 2, RDW, initial SOFA score, and MAP were significantly correlated with sepsis-induced AKI (AUC: 0.712, 95% CI: 0.651-0.774). In Model 3, NLR, initial SOFA score, and MAP were significantly correlated with sepsis-induced AKI (AUC: 0.719, 95% CI: 0.658-0.780). Our novel models, integrating MDW, RDW, and NLR with initial SOFA score and MAP, can assist with the identification of sepsis-induced AKI among patients with sepsis presenting to the ED.

Synthesis and characterization of targeted 17ß-hydroxysteroid dehydrogenase type 7 inhibitors.

Sex steroid hormones such as estrogen estradiol (E2) and androgen dihydrotestosterone (DHT) are involved in the development of hormone-dependent cancers. Blockade of 17ß-hydroxysteroid dehydrogenase type 7 (17ß-HSD7), a member of the short chain dehydrogenase/reductase superfamily, is thought to decrease E2 levels while increasing those of DHT. Therefore, its unique double action makes this enzyme as an interesting drug target for treatment of breast cancer. The chemical synthesis, molecular characterization, and preliminary biological evaluation as 17ß-HSD7 inhibitors of novel carbamate derivatives 3 and 4 are described. Like previous 17ß-HSD7 inhibitors 1 and 2, compounds 3 and 4 bear a hydrophobic nonyl side chain at the C-17ß position of a 4-aza-5α-androstane nucleus, but compound 3 has an oxygen atom replacing the CH2 in the steroid A-ring C-2 position, while compound 4 has a C17-spiranic E-ring containing a carbamate function. They both inhibited the in vitro transformation of estrone (E1) into E2 by 17ß-HSD7, but the introduction of a (17 R)-spirocarbamate is preferable to replacing C-2 methylene with an oxygen atom since compound 4 (IC50 = 63 nM) is an inhibitor 14 times more powerful than compound 3 (IC50 = 900 nM). Furthermore, when compared to the reference inhibitor 1 (IC50 = 111 nM), the use of a C17-spiranic E-ring made it possible to introduce differently the hydrophobic nonyl side chain, without reducing the inhibitory activity.

Long-COVID impacts taste and olfactory in individuals with substance use disorder: A retrospective cohort study from the TriNetX US Collaborative Networks.

Substance use disorder (SUD) exacerbates the impact of Long-COVID, particularly increasing the risk of taste and olfactory disorders. Analyzing retrospective cohort data from TriNetX and over 33 million records (Jan 2020-Dec 2022), this study focused on 1,512,358 participants, revealing that SUD significantly heightens the likelihood of experiencing taste disturbances and anosmia in Long-COVID sufferers. Results indicated that individuals with SUD face a higher incidence of sensory impairments compared to controls, with older adults and women being particularly vulnerable. Smokers with SUD were found to have an increased risk of olfactory and taste dysfunctions. The findings underscore the importance of early screening, diagnosis, and interventions for Long-COVID patients with a history of SUD, suggesting a need for clinicians to monitor for depression and anxiety linked to sensory dysfunction for comprehensive care.

Clinical Characteristics and Outcomes of the Phenotypes of COPD-Bronchiectasis Association.

INTRODUCTION: Although COPD may frequently co-exist with bronchiectasis [COPD-bronchiectasis associated (CBA)], little is known regarding the clinical heterogeneity. We aimed to identify the phenotypes and compare the clinical characteristics and prognosis of CBA. METHODS: We conducted a retrospective cohort study involving 2928 bronchiectasis patients, 5158 COPD patients, and 1219 patients with CBA hospitalized between July 2017 and December 2020. We phenotyped CBA with a two-step clustering approach and validated in an independent retrospective cohort with decision-tree algorithms. RESULTS: Compared with patients with COPD or bronchiectasis alone, patients with CBA had significantly longer disease duration, greater lung function impairment, and increased use of intravenous antibiotics during hospitalization. We identified five clusters of CBA. Cluster 1 (N=120, CBA-MS) had predominantly moderate-severe bronchiectasis, Cluster 2 (N=108, CBA-FH) was characterized by frequent hospitalization within the previous year, Cluster 3 (N=163, CBA-BI) had bacterial infection, Cluster 4 (N=143, CBA-NB) had infrequent hospitalization but no bacterial infection, and Cluster 5 (N=113, CBA-NHB) had no hospitalization or bacterial infection in the past year. The decision-tree model predicted the cluster assignment in the validation cohort with 91.8% accuracy. CBA-MS, CBA-BI, and CBA-FH exhibited higher risks of hospital re-admission and intensive care unit admission compared with CBA-NHB during follow-up (all P<0.05). Of the five clusters, CBA-FH conferred the worst clinical prognosis. CONCLUSION: Bronchiectasis severity, recent hospitalizations and sputum culture findings are three defining variables accounting for most heterogeneity of CBA, the characterization of which will help refine personalized clinical management.

Analyzing the changing trend of corneal biomechanical properties under different influencing factors in T2DM patients.

To analyze the changing trend of CH and CRF values under different influencing factors in T2DM patients. A total of 650 patients with T2DM were included. We discovered that the course of T2DM, smoking history, BMI, and FBG, DR, HbA1c, TC, TG, and LDL-C levels were common risk factors for T2DM, while HDL-C levels were a protective factor. Analyzing the CH and CRF values according to the course of diabetes, we discovered that as T2DM continued to persist, the values of CH and CRF gradually decreased. Moreover, with the increase in FBG levels and the accumulation of HbA1c, the values of CH and CRF gradually decreased. In addition, in patients with HbA1c (%) > 12, the values of CH and CRF decreased the most, falling by 1.85 ± 0.33 mmHg and 1.28 ± 0.69 mmHg, respectively. Compared with the non-DR group, the CH and CRF values gradually decreased in the mild-NPDR, moderate-NPDR, severe-NPDR and PDR groups, with the lowest CH and CRF values in the PDR group. In patients with T2DM, early measurement of corneal biomechanical properties to evaluate the change trend of CH and CRF values in different situations will help to identify and prevent diabetic keratopathy in a timely manner.

Effects of Reishimmune-S, a Fungal Immunomodulatory Peptide Supplement, on the Quality of Life and Circulating Natural Killer Cell Profiles of Patients With Early Breast Cancer Receiving Adjuvant Endocrine Therapy.

OBJECTIVES: To evaluate the effects of Reishimmune-S, a fungal immunomodulatory peptide, on the quality of life (QoL) and natural killer (NK) cell subpopulations in patients receiving adjuvant endocrine therapy (ET) for breast cancer (BC). METHODS: Patients who received adjuvant ET for stage I-III hormone receptor-positive BC without active infection were enrolled in this prospective pilot study. Reishimmune-S was administered sublingually daily for 6 months. QoL scores, circulating immune cell levels, including lymphocyte/NK cell subpopulations, and plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were measured at baseline and every 4 weeks. Data were analyzed using linear mixed-effect regression models. RESULTS: Nineteen participants were included in the analyses. One patient with underlying asthma did not complete the study owing to the occurrence of skin rashes 15 days after the initiation of Reishimmune-S. No other adverse events were reported. Reishimmune-S supplementation significantly improved the cognitive function at 3 months and significantly decreased the fatigue and insomnia levels at 3 and 6 months, respectively. There was no significant change in the global health/QoL score between baseline and week 4 of treatment. The proportion of CD19+ lymphocytes was significantly higher at 3 and 6 months, and that of NKG2A+ and NKp30+ NK cells was significantly lower at 6 months than at baseline. In addition, fatigue positively correlated with the proportion of NKp30+ NK cells (ß ± standard error: 24.48 ± 8.75, P = .007 in the mixed-effect model). CONCLUSIONS: Short-term supplementation with Reishimmune-S affected the circulating immune cell composition and exerted positive effects on cognitive function, fatigue, and insomnia in patients with BC undergoing adjuvant ET, providing a potential approach for the management of treatment-related adverse reactions in this patient population.

Simple and sensitive sandwich-like electrochemical immunosensing strategy for D-dimer based on cyclodextrin-carbon nanotube and nanogold-ferrocene.

D-dimer is a very important biomarker about sepsis, pulmonary thromboembolism and atherosclerosis, thus designing effective and sensitive method for its detection is of great significance. Herein, by synthesizing ß-cyclodextrin-carbon nanotube nanohybrid (CNTs-CD) as the carrier to assemble the initial antibody (Ab1) of D-dimer, immobilizing secondary antibody (Ab2) and sulfydryl ferrocene (Fc) on the nanogold (Au) particles surface as the signaling amplifier (Ab2-Au-Fc), a low cost, simple, sensitive and effective sandwich-like electrochemical immunosensing (SEI) platform of D-dimer was proposed in this work for the first time. Briefly, CNTs shows large specific area and superior electroconductivity, and CD provides high host guest recognition ability that could bound with Ab1; meanwhile, the Fc probe offers stable current response which are proportionable positively to the level of D-dimer. Under the best conditions, the designed SEI platform exhibits prominent analytical performances for D-dimer: low detection limit of 3.0 ng mL-1 and large linearity of 10.0-800.0 ng mL-1. In addition, the selectivity, stability and reproducibility as well as real applications of the proposed SEI assay were evaluated and the obtained results are satisfactory.

A new resorcylic acid lactone from the endophytic fungus Chaetosphaeronema sp.

A new 14-membered resorcylic acid lactone (RAL14), chaetolactone A (1), along with three known ones (2-4), was obtained from the fermentation of the soil-derived fungus Chaetosphaeronema sp. SSJZ001. Their structures were established based on extensive spectroscopic data analyses (UV, IR, HRESIMS, 1D, and 2D NMR),13C NMR chemical shifts calculations coupled with the DP4+ probability method, theoretical calculations of ECD spectra, as well as X-ray diffraction analysis. All compounds were evaluated for their cytotoxic effects against A549, HO-8910, and MCF-7 cell lines.

The Prognostic Value of Positron Emission Tomography/Computed Tomography in Clinical Stage I Lung Cancer Patients: A Propensity-Match Analysis.

Background: The application of positron emission tomography/computed tomography (PET/CT) helps provide accurate clinical staging for lung cancer patients. However, the effects and trends in early-stage lung cancer remain unclear. The aim of this study was to compare differences between clinical stage I lung cancer patients who received PET/CT for staging and those who did not. Methods: Data were obtained from the Taiwan Society of Cancer Registry. There were 6587 clinical stage I lung cancer patients between 2009 and 2014 analyzed in this study. We compared the characteristics of the PET/CT and no PET/CT groups. After propensity score matching, it resulted in both groups having 2649 patients. We measured the overall survival rates of all clinical stage I lung cancer patients and the overall survival rates of patients with PET/CT and without PET/CT. Results: The 1-, 3-, and 5-year survival rates of all clinical stage I lung cancer patients were 97.2%, 88.2%, and 79.0%, respectively. Patients with a larger tumor size tended to receive PET/CT for staging (stage Ib: 38.25% vs. 27.82%, p < 0.0001) and a larger resection (lobectomy: 74.62% vs. 66.61%, p < 0.0001). The 5-year survival rates were 79.8% in the PET/CT group and 78.2% in the no PET/CT group after propensity score matching (p = 0.6528). Conclusions: For clinical stage I lung cancer in Taiwan, patients with larger tumor sizes tend to have PET/CT for staging. Although PET/CT provided more precise clinical staging, these patients still received larger resections and had more pathological migration. However, there was no overall survival rate benefit after PET/CT.

Oleanane and 30-noroleanane triterpenoids from the roots of Paeonia lactiflora.

An investigation of EtOAc extract from the roots of Paeonia lactiflora yielded three new 30-noroleanane triterpenoids paeonenoides L-N (1-3) and one new oleanane triterpenoid paeonenoide O (4) together with 7 known compounds (5-11). Extensive spectrographic experiments were applied to identify the structures of 1-4, and their absolute configurations were unambiguously determined by theoretical calculations of ECD spectra, as well as the single-crystal X-ray diffraction analysis. Compounds 8, 9 and 10 were isolated from the Paeonia genus for the first time. Moreover, compounds 8, 9 and 11 showed inhibitory activities against LPS-induced nitric oxide (NO) production in RAW264.7 macrophages with the IC50 values of 72. 17 ± 4.74, 30.02 ± 2.03 and 28.34 ± 1.85 µM, respectively.

Using machine learning to identify key subject categories predicting the pre-clerkship and clerkship performance: 8-year cohort study.

BACKGROUND: Medical students need to build a solid foundation of knowledge to become physicians. Clerkship is often considered the first transition point, and clerkship performance is essential for their development. We hope to identify subjects that could predict the clerkship performance, thus helping medical students learn more efficiently to achieve high clerkship performance. METHODS: This cohort study collected background and academic data from medical students who graduated between 2011 and 2019. Prediction models were developed by machine learning techniques to identify the affecting features in predicting the pre-clerkship performance and clerkship performance. Following serial processes of data collection, data preprocessing before machine learning, and techniques and performance of machine learning, different machine learning models were trained and validated using the 10-fold cross-validation method. RESULTS: Thirteen subjects from the pre-med stage and 10 subjects from the basic medical science stage with an area under the ROC curve (AUC) >0.7 for either pre-clerkship performance or clerkship performance were found. In each subject category, medical humanities and sociology in social science, chemistry, and physician scientist-related training in basic science, and pharmacology, immunology-microbiology, and histology in basic medical science have predictive abilities for clerkship performance above the top tertile. Using a machine learning technique based on random forest, the prediction model predicted clerkship performance with 95% accuracy and 88% AUC. CONCLUSION: Clerkship performance was predicted by selected subjects or combination of different subject categories in the pre-med and basic medical science stages. The demonstrated predictive ability of subjects or categories in the medical program may facilitate students' understanding of how these subjects or categories of the medical program relate to their performance in the clerkship to enhance their preparedness for the clerkship.

Advancing Lithium Battery Performance through Porous Conductive Polyaniline-Modified Graphene Composites Additive.

This study aimed to enhance lithium battery performance through the utilization of porous conductive polyaniline-modified graphene composites (PMGCs). Given the growing importance of green energy, coupled with the development of lithium-ion battery systems and electric vehicles, achieving high-speed charge and discharge performance is imperative. Traditional approaches involve incorporating additives like carbon nanotubes and graphene into electrodes to improve conductivity, but they encounter challenges related to cost and aggregation issues. In this study, polyaniline (PANI), a cost-effective, stable, and conductive polymer, was explored. PMGCs was formed by employing ammonium persulfate (APS) as an oxidant during PANI polymerization, simultaneously serving as a surface modifier for graphene. This study systematically investigated the impacts of varying amounts of PMGCs on lithium-ion battery electrodes by assessing the reductions in internal resistance, aging effects, different charge and discharge rates, and cycle performance. The PMGC exhibited a porous structure formed by nanoscale PANI intertwining on graphene. Various measurements, including FT-IR, TGA, Raman spectroscopy, and battery performance assessments, confirmed the successful synthesis and positive effects of PMGCs. The results indicated that a 0.5% addition of PMGC led to a reduced internal resistance and enhanced fast-charge and discharge capacity. However, an excessive amount of PMGCs adversely affected aging and self-discharge. This study provides valuable insights into optimizing the PMGC content for improved lithium battery performance, presenting potential advancements in energy storage systems and electric vehicles.

Leveraging molecular targeted drugs and immune checkpoint inhibitors treat advanced thyroid carcinoma to achieve thyroid carcinoma redifferentiation.

Thyroid cancer can be classified into three different types based on the degree of differentiation: well-differentiated, poorly differentiated, and anaplastic thyroid carcinoma. Well-differentiated thyroid cancer refers to cancer cells that closely resemble normal thyroid cells, while poorly differentiated and anaplastic thyroid carcinoma are characterized by cells that have lost their resemblance to normal thyroid cells. Advanced thyroid carcinoma, regardless of its degree of differentiation, is known to have a higher likelihood of disease progression and is generally associated with a poor prognosis. However, the process through which well-differentiated thyroid carcinoma transforms into anaplastic thyroid carcinoma, also known as "dedifferentiation", has been a subject of intensive research. In recent years, there have been significant breakthroughs in the treatment of refractory advanced thyroid cancer. Clinical studies have been conducted to evaluate the efficacy and safety of molecular targeted drugs and immune checkpoint inhibitors in the treatment of dedifferentiated thyroid cancer. These drugs work by targeting specific molecules or proteins in cancer cells to inhibit their growth or by enhancing the body's immune response against the cancer cells. This article aims to explore some of the possible mechanisms behind the dedifferentiation process in well-differentiated thyroid carcinoma. It also discusses the clinical effects of molecular targeted drugs and immune checkpoint inhibitors in thyroid cancer patients with different degrees of differentiation. Furthermore, it offers insights into the future trends in the treatment of advanced thyroid cancer, highlighting the potential for improved outcomes and better patient care.

Activation of free fatty acid receptors, FFAR1 and FFAR4, ameliorates ulcerative colitis by promote fatty acid metabolism and mediate macrophage polarization.

OBJECTIVE: To investigate the mechanism of action of fatty acid receptors, FFAR1 and FFAR4, on ulcerative colitis (UC) through fatty acid metabolism and macrophage polarization. METHODS: Dextran sulfate sodium (DSS)-induced mouse model of UC mice was used to evaluate the efficacy of FFAR1 (GW9508) and FFAR4 (GSK137647) agonists by analyzing body weight, colon length, disease activity index (DAI), and histological scores. Real-time PCR and immunofluorescence analysis were performed to quantify the levels of fatty acid metabolizing enzymes and macrophage makers. FFA-induced lipid accumulation in RAW264.7 cells was visualized by Oil Red O staining analysis, and cells were collected to detect macrophage polarization by flow cytometry. RESULTS: The combination of GW9508 and GSK137647 significantly improved DSS-induced UC symptoms, caused recovery in colon length, and decreased histological injury. GW9508 + GSK137647 treatment upregulated the expressions of CD206, lipid oxidation enzyme (CPT-1α) and anti-inflammatory cytokines (IL-4, IL-10, IL-13) but downregulated those of CD86, lipogenic enzymes (ACC1, FASN, SCD1), and pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α). Combining the two agonists decreased FFA-induced lipid accumulation and increased CD206 expression in cell-based experiments. CONCLUSION: Activated FFAR1 and FFAR4 ameliorates DSS-induced UC by promoting fatty acid metabolism to reduce lipid accumulation and mediate M2 macrophage polarization.