Lipid levels and insulin resistance markers in gastric cancer patients: diagnostic and prognostic significance.

Gastric cancer (GC) is a highly heterogeneous and aggressive malignant tumor that seriously affects the life safety of people all over the world. Its early manifestations are subtle. The present study aimed to investigate the clinical significance of serum lipid profiles, insulin resistance markers including the triglyceride-glucose (TyG) index and the atherosclerotic index (AI), in GC patients. A retrospective analysis encompassed 215 GC patients and 827 healthy individuals. The study results show that the total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein levels, and the TyG index of GC patients were significantly lower than those of the control group before and after propensity score matching analysis. In the GC group, the levels of CEA, CA199, CA125, and CA724 tumor markers were higher than those in the healthy control group. Patients in advanced stages exhibited lower serum levels of serum lipids and TyG index compared to those in early stages. ROC analysis revealed that the TyG index, CA125, and CA199 combination yielded the highest positive prediction rate for GC at 98.6%. TyG index is significantly associated with the risk of adverse reactions after chemotherapy (OR = 1.104, 95% CI 1.028-1.186, P < 0.01). Multiple tumor markers and the TyG index combined detection showed correlations with five adverse reactions caused by chemotherapy (r < 0.6, P < 0.05). Preoperative lipid profiles in the serum show a strong correlation with patients diagnosed with GC. Evaluating a combination of various serum lipids and cancer markers significantly improves diagnostic precision for GC and the ability to predict chemotherapy side effects.

CTR-FAPI PET enables precision management of medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but 29-60% patients failed to localize the disease in the current clinical practice. Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head compared [68Ga]Ga-CTR-FAPI PET-CT and [18F]FDG PET-CT in 50 MTC patients. The primary endpoint was the patient-based detection rate, with [68Ga]Ga-CTR-FAPI exhibiting higher detection than [18F]FDG (98% vs. 66%, p=0.0002). This improved detection was attributed to increased tumor uptake (SUVmax 11.71±9.16 vs. 2.55±1.73, p<0.0001). Diagnostic accuracy, validated on lesions with gold-standard pathology, was greater for [68Ga]Ga-CTR-FAPI compared to [18F]FDG (96.7% vs. 43.3%, p<0.0001). Notably, 32% patients altered management following [68Ga]Ga-CTR-FAPI PET-CT, and 66.7% patients changed their surgical plan. Overall, [68Ga]Ga-CTR-FAPI PET-CT provided superior detection and diagnostic accuracy compared to [18F]FDG PET-CT, enabling precision management of MTC patients.

Mapping Reaction Pathways by In Situ Step Sweep Voltammetry Flow Electrochemical Mass Spectrometry.

A step sweep voltammetry (SSV) flow electrochemical (EC) mass spectrometry (MS) platform was developed for real-time and in situ mapping of EC reaction pathways. By integrating a flow EC cell into the pneumatic spray nozzle followed by atmospheric chemical ionization, this setup was capable of in situ MS monitoring of short-lived EC intermediates with enhanced sensitivity. This setup also realized precise measurement and control of the electrode potential during in situ EC-MS analysis, which can provide detailed information on the interplay of reaction pathways under different electrode potentials. Taking the EC reductive cross coupling of nitroarenes with arylboronic acids as an example, SSV-MS had identified 13 compounds among four reaction pathways. Among these, the electrode potential of active nitrene and cross coupling intermediates were measured for the first time and the structure of the nitroso coupling complex was also confirmed by MS. With the systematic measurement of electrode potential of the intermediates and products, SSV-MS had clearly mapped out the synergies and competitions between different reaction pathways, offering key insights for optimizing reaction conditions and investigating reaction mechanisms for EC research.

Identifying modifiable factors and their joint effect on frailty: a large population-based prospective cohort study.

A thorough understanding and identification of potential determinants leading to frailty are imperative for the development of targeted interventions aimed at its prevention or mitigation. We investigated the potential determinants of frailty in a cohort of 469,301 UK Biobank participants. The evaluation of frailty was performed using the Fried index, which encompasses measurements of handgrip strength, gait speed, levels of physical activity, unintentional weight loss, and self-reported exhaustion. EWAS including 276 factors were first conducted. Factors associated with frailty in EWAS were further combined to generate composite scores for different domains, and joint associations with frailty were evaluated in a multivariate logistic model. The potential impact on frailty when eliminating unfavorable profiles of risk domains was evaluated by PAFs. A total of 21,020 (4.4%) participants were considered frailty, 192,183 (41.0%) pre-frailty, and 256,098 (54.6%) robust. The largest EWAS identified 90 modifiable factors for frailty across ten domains, each of which independently increased the risk of frailty. Among these factors, 67 have the potential to negatively impact health, while 23 have been found to have a protective effect. When shifting all unfavorable profiles to intermediate and favorable ones, overall adjusted PAF for potentially modifiable frailty risk factors was 85.9%, which increases to 86.6% if all factors are transformed into favorable tertiles. Health and medical history, psychosocial factors, and physical activity were the most significant contributors, accounting for 11.9%, 10.4%, and 10.1% respectively. This study offers valuable insights for developing population-level strategies aimed at preventing frailty.

A Bis-Boron Amino Acid for Positron Emission Tomography and Boron Neutron Capture Therapy.

Trifluoroborate boronophenylalanine (BBPA) is a boron amino acid analog of 4­boronophenylalanine (BPA) but with a trifluoroborate group (-BF3-) instead of a carboxyl group (-COOH). Clinical studies have shown that 18F-labeled BBPA ([18F]BBPA) can produce high-contrast tumor images in positron emission tomography (PET). Beyond PET imaging, BBPA is a theranostic agent for boron neutron capture therapy (BNCT). Because BBPA possesses an identical chemical structure to BNCT and PET, it can potentially predict the boron concentration for BNCT using [18F]BBPA-PET. The synthesis of BBPA was achieved by selectively fluorinating the α-aminoborate compound, taking advantage of the varying rates of solvolysis of the B-F bond. The study showcased the high-contrast [18F]BBPA-PET imaging in various tumor models, highlighting its broad applicability for both [18F]BBPA-PET and BBPA-BNCT. [18F]BBPA-PET tumor uptake remains consistent across various doses, including those used in BNCT. This enables accurate estimation of the boron concentration in tumors using [18F]BBPA-PET. With its dual boron structure, BBPA increases boron concentration in tumor cells and tumor tissues compared to BPA. Thus, less boron carrier is needed. This study introduces a new theranostic boron carrier that enhances boron accumulation in tumors, predicts boron concentration, and enhances the accuracy and effectiveness of BNCT.

Transcriptomic decoding of regional cortical vulnerability to major depressive disorder.

Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.

Bipolar disorder and oxidative stress: A bibliometric perspective.

OBJECTIVE: Accumulating evidence indicates that oxidative stress and the disruption of antioxidant defenses play an important role in the neurobiology of bipolar disorder (BD). Studies have found that increased oxidative stress may be associated with cell apoptosis and neuronal damage in BD patients. Hence, this study explored the research field related to BD and oxidative stress from a bibliometrics perspective. METHODS: Literature search and relevant data retrieval based on the Web of Sciences Core Collection (WoSCC). R software (version 4.2.2), VOSviewer software (version 1.6.18), and CiteSpace (version 6.1.6) were used in this bibliometric analysis. RESULTS: A total of 2081 publications related to BD and oxidative stress were published between 1986 and 2024. Bipolar Disorders was the journal that had the most publications in this area (72; 3.46%; IF = 5.9), while the United States (1285; 61.7%) and the University of Toronto (377; 18.1%) were the most productive country and institution, respectively. Apart from "oxidative stress" and "bipolar disorder," the most frequently used keywords were "schizophrenia," "prefrontal cortex," and "nitric oxide." CONCLUSIONS: The growing number of publications related to BD and oxidative stress in recent years highlights the importance of this research field. Hot topics in research related to BD and oxidative stress included animal experiments and molecular mechanisms, psychiatric-related inflammation and biomarkers, neurodegenerative diseases, and metabolism. Furthermore, the biological mechanisms of BD, particularly biomarkers and inflammation, may be the emerging research priority area in the future.

Locally unlocks prodrugs by radiopharmaceutical in tumor for cancer therapy.

Chemotherapy is the first-line treatment for cancer, but its systemic toxicity can be severe. Tumor-selective prodrug activation offers promising opportunities to reduce systemic toxicity. Here, we present a strategy for activating prodrugs using radiopharmaceuticals. This strategy enables the targeted release of chemotherapeutic agents due to the high tumor-targeting capability of radiopharmaceuticals. [18F]FDG (2-[18F]-fluoro-2-deoxy-D-glucose), one of the most widely used radiopharmaceuticals in clinics, can trigger Pt(IV) complex for controlled release of axial ligands in tumors, it might be mediated by hydrated electrons generated by water radiolysis resulting from the decay of radionuclide 18F. Its application offers the controlled release of fluorogenic probes and prodrugs in living cells and tumor-bearing mice. Of note, an OxaliPt(IV) linker is designed to construct an [18F]FDG-activated antibody-drug conjugate (Pt-ADC). Sequential injection of Pt-ADC and [18F]FDG efficiently releases the toxin in the tumor and remarkably suppresses the tumor growth. Radiotherapy is booming as a perturbing tool for prodrug activation, and we find that [18F]FDG is capable of deprotecting various radiotherapy-removable protecting groups (RPGs). Our results suggest that tumor-selective radiopharmaceutical may function as a trigger, for developing innovative prodrug activation strategies with enhanced tumor selectivity.

Arbuscular mycorrhizal fungi regulate amino acid metabolism, phytohormones and glycolysis pathway to promote the growth of Suaeda salsa under combined Cd and NaCl stresses.

The use of halophytes in conjunction with arbuscular mycorrhizal (AM) fungi has been found to enhance the removal efficacy of heavy metals and salts in heavy metals contaminated saline soil. The mechanisms of AM fungi on promoting halophyte growth and regulating metabolism remain unclear. In this study, combinations of 0 g kg-1 NaCl and 3 mg kg-1 Cd (S0Cd3), 6 g kg-1 NaCl and 3 mg kg-1 Cd (S6Cd3), and 12 g kg-1 NaCl and 3 mg kg-1 Cd (S12Cd3) were employed to explore the impact of Funneliformis mosseae on the growth and metabolism of Suaeda salsa. The results showed that AM fungi increased the biomass and the P, K+, Ca2+, and Mg2+ accumulations, reduced the Cd and Na+ concentrations in S0Cd3 and S6Cd3, and increased the Cd concentrations in S12Cd3. AM fungi inoculation reduced the Cd and Na+ transfer factors and increased the Cd and Na+ accumulations in S6Cd3. The metabolomics of S6Cd3 showed that AM fungi upregulated the expression of 5-hydroxy-L-tryptophan and 3-indoleacid acid in tryptophan metabolism, potentially acting as crucial antioxidants enabling plants to actively cope with abiotic stresses. AM fungi upregulated the expression of arbutin in glycolysis process, enhancing the plants' osmoregulation capacity. AM fungi upregulated the expression of 2-hydroxycinnamic acid in phenylalanine metabolism and dopaquinone in tyrosine metabolism. These two metabolites help effectively remove reactive oxygen species. Correspondingly, AM fungi decreased MDA content and increased soluble sugar content. These results indicate that AM fungi improve the stress resistance of S. salsa by increasing nutrient uptake and regulating physiological and metabolic changes.

A Study on the Removal of Impurity Elements Silicon and Zinc from Rubidium Chloride by Vacuum Distillation.

With the rapid development of high and new technology, rubidium and its compounds show broad application prospect and market demand with their unique characteristics. At present, the production of rubidium metal is mainly prepared by calcium thermal reduction of rubidium chloride. Rubidium metal obtained by reduction requires multi-step vacuum distillation to obtain high-purity rubidium metal. The purity of rubidium metal depends on the purity of the raw material rubidium chloride. Rubidium metal is relatively active and is easy to oxidize and explode in air. Therefore, a method combining vacuum decomposition and vacuum distillation to reduce impurity elements in rubidium chloride from raw materials is proposed in this paper. The experimental results show that under the conditions of pressure of 5-10 Pa, distillation temperature of 823 K and vacuum distillation time of 60 min, the contents of Si and Zn impurities are reduced from 1206 mg/kg and 310 mg/kg to less than 0.1 mg/kg, and the removal rates are 99.99% and 99.97%, respectively. Rubidium chloride has almost no loss, and through one-step vacuum distillation, the impurity elements silicon and zinc can be deeply removed, reducing the flammability and explosiveness, high cost, long process and other problems caused by the subsequent preparation of high-purity rubidium metal.

A novel approach for sludge deep-dewatering via flowing-out enhancement but not relying on cell lysis and bound water release.

Effective deep-dewatering is crucial for wastewater sludge management. Currently, the dominant methods focus on promoting cell lysis to release intracellular water, but these techniques often lead to secondary pollution and require stringent conditions, limiting their practical use. This study explores an innovative method using a commercially available complex quaternary ammonium salt surfactant, known as G-agent. This agent remarkably reduces the sludge water content from 98.6 % to 56.8 % with a low dosage (50 mg/g DS) and under neutral pH conditions. This approach surpasses Fenton oxidation in terms of dewatering efficiency and avoids the necessity for cell lysis and bound water release, thereby reducing the risk of secondary pollution in the filtrate, including heavy metals, nitrogen, phosphorus, and other contaminants. The G-agent plays a significant role in destabilizing flocs and enhancing flocculation during the conditioning and initial dewatering stages, effectively reducing the solid-liquid interfacial affinity of the sludge. In the compression filtration stage, the agent's solidification effect is crucial in forming a robust skeleton that improves pore connectivity within the filter cake, leading to increased water permeability, drainage performance and water flow-out efficiency. This facilitates deep dewatering of sludge without cell lysis. The study reveals that the G-agent primarily improves water flow-out efficiency rather than water flowability, indicating that cell lysis and bound water release are not indispensable prerequisites for sludge deep-dewatering. Furthermore, it presents an encouraging prospect for overcoming the limitations associated with conventional sludge deep-dewatering processes.

Covalent targeted radioligands potentiate radionuclide therapy.

Targeted radionuclide therapy, in which radiopharmaceuticals deliver potent radionuclides to tumours for localized irradiation, has addressed unmet clinical needs and improved outcomes for patients with cancer1-4. A therapeutic radiopharmaceutical must achieve both sustainable tumour targeting and fast clearance from healthy tissue, which remains a major challenge5,6. A targeted ligation strategy that selectively fixes the radiopharmaceutical to the target protein in the tumour would be an ideal solution. Here we installed a sulfur (VI) fluoride exchange (SuFEx) chemistry-based linker on radiopharmaceuticals to prevent excessively fast tumour clearance. When the engineered radiopharmaceutical binds to the tumour-specific protein, the system undergoes a binding-to-ligation transition and readily conjugates to the tyrosine residues through the 'click' SuFEx reaction. The application of this strategy to a fibroblast activation protein (FAP) inhibitor (FAPI) triggered more than 80% covalent binding to the protein and almost no dissociation for six days. In mice, SuFEx-engineered FAPI showed 257% greater tumour uptake than did the original FAPI, and increased tumour retention by 13-fold. The uptake in healthy tissues was rapidly cleared. In a pilot imaging study, this strategy identified more tumour lesions in patients with cancer than did other methods. SuFEx-engineered FAPI also successfully achieved targeted ß- and α-radionuclide therapy, causing nearly complete tumour regression in mice. Another SuFEx-engineered radioligand that targets prostate-specific membrane antigen (PSMA) also showed enhanced therapeutic efficacy. Considering the broad scope of proteins that can potentially be ligated to SuFEx warheads, it might be possible to adapt this strategy to other cancer targets.

Prevalence and network structure of depression, insomnia and suicidality among mental health professionals who recovered from COVID-19: a national survey in China.

Psychiatric syndromes are common following recovery from Coronavirus Disease 2019 (COVID-19) infection. This study investigated the prevalence and the network structure of depression, insomnia, and suicidality among mental health professionals (MHPs) who recovered from COVID-19. Depression and insomnia were assessed with the Patient Health Questionnaire (PHQ-9) and Insomnia Severity Index questionnaire (ISI7) respectively. Suicidality items comprising suicidal ideation, suicidal plan and suicidal attempt were evaluated with binary response (no/yes) items. Network analyses with Ising model were conducted to identify the central symptoms of the network and their links to suicidality. A total of 9858 COVID-19 survivors were enrolled in a survey of MHPs. The prevalence of depression and insomnia were 47.10% (95% confidence interval (CI) = 46.09-48.06%) and 36.2% (95%CI = 35.35-37.21%), respectively, while the overall prevalence of suicidality was 7.8% (95%CI = 7.31-8.37%). The key central nodes included "Distress caused by the sleep difficulties" (ISI7) (EI = 1.34), "Interference with daytime functioning" (ISI5) (EI = 1.08), and "Sleep dissatisfaction" (ISI4) (EI = 0.74). "Fatigue" (PHQ4) (Bridge EI = 1.98), "Distress caused by sleep difficulties" (ISI7) (Bridge EI = 1.71), and "Motor Disturbances" (PHQ8) (Bridge EI = 1.67) were important bridge symptoms. The flow network indicated that the edge between the nodes of "Suicidality" (SU) and "Guilt" (PHQ6) showed the strongest connection (Edge Weight= 1.17, followed by "Suicidality" (SU) - "Sad mood" (PHQ2) (Edge Weight = 0.68)). The network analysis results suggest that insomnia symptoms play a critical role in the activation of the insomnia-depression-suicidality network model of COVID-19 survivors, while suicidality is more susceptible to the influence of depressive symptoms. These findings may have implications for developing prevention and intervention strategies for mental health conditions following recovery from COVID-19.

[Stellera chamaejasme against multidrug resistance of triple-negative breast cancer MDA-MB-231 cell through Nrf2].

This study aims to investigate the effect and mechanism of Stellera chamaejasme extract(SCL) on multidrug resistance(MDR) in breast cancer. Human triple-negative breast cancer cell line MDA-MB-231 and its adriamycin-resistant cell line MDA-MB-231/ADR were used in the experiment. Cell viability was detected by methyl thiazolyl tetrazolium(MTT) assay, and cell apoptosis was detected by DAPI staining and Annexin-V/Pi double staining. Western blot(WB) was used to detect the expression levels of Keap1, Nrf2, HO-1, Bcl-2, Bax, caspase-9, and caspase-3. Immunofluorescence staining was used to observe the distribution of Nrf2 in the cell, and flow cytometry was used to detect the level of reactive oxygen species(ROS) in the cell. The results showed that the resis-tance factor of SCL was 0.69, and that of adriamycin and paclitaxel was 8.40 and 16.36, respectively. DAPI staining showed that SCL could cause nuclear shrinkage and fragmentation of breast cancer cells. Annexin-V/Pi double staining showed that the average apoptosis rate of the drug-resistant cells was 32.64% and 50.29%, respectively under medium and high doses of SCL. WB results showed that SCL could significantly reduce the expression levels of anti-apoptotic proteins Bcl-2, caspase-9, and caspase-3 and significantly increase the expression level of pro-apoptotic protein Bax. Further studies showed that SCL could significantly promote the expression of Keap1, significantly inhibit the expression of Nrf2 and HO-1, and significantly reduce the expression level of Nrf2 in the nucleus. Correspondingly, flow cytometry showed that the intracellular ROS level was significantly increased. In conclusion, SCL can significantly inhibit the proliferation of MDA-MB-231 multidrug-resistant cells of triple-negative breast cancer and cause cell apoptosis, and the mechanism is related to inhibiting Keap1/Nrf2 signaling pathway, leading to ROS accumulation in drug-resistant cells and increasing the expression of apoptosis-related proteins.

Piezocatalytically-induced controllable mineralization scaffold with bone-like microenvironment to achieve endogenous bone regeneration.

Orderly hierarchical structure with balanced mechanical, chemical, and electrical properties is the basis of the natural bone microenvironment. Inspired by nature, we developed a piezocatalytically-induced controlled mineralization strategy using piezoelectric polymer poly-L-lactic acid (PLLA) fibers with ordered micro-nano structures to prepare biomimetic tissue engineering scaffolds with a bone-like microenvironment (pcm-PLLA), in which PLLA-mediated piezoelectric catalysis promoted the in-situ polymerization of dopamine and subsequently regulated the controllable growth of hydroxyapatite crystals on the fiber surface. PLLA fibers, as analogs of mineralized collagen fibers, were arranged in an oriented manner, and ultimately formed a bone-like interconnected pore structure; in addition, they also provided bone-like piezoelectric properties. The uniformly sized HA nanocrystals formed by controlled mineralization provided a bone-like mechanical strength and chemical environment. The pcm-PLLA scaffold could rapidly recruit endogenous stem cells, and promote their osteogenic differentiation by activating cell membrane calcium channels and PI3K signaling pathways through ultrasound-responsive piezoelectric signals. In addition, the scaffold also provided a suitable microenvironment to promote macrophage M2 polarization and angiogenesis, thereby enhancing bone regeneration in skull defects of rats. The proposed piezocatalytically-induced controllable mineralization strategy provides a new idea for the development of tissue engineering scaffolds that can be implemented for multimodal physical stimulation therapy.

The impact of SARS-Cov-2 Omicron infection on short-term outcomes after elective surgery in patients with gastrointestinal cancer.

With the emergence of novel variants, Omicron variant caused a different clinical picture than the previous variants and little evidence was reported regarding perioperative outcomes after Omicron variants. The aim of the study was to evaluate the postoperative outcomes of gastrointestinal cancer patients following Omicron variants infection and also to determine the timing of surgery after infection recovery. A total of 124 patients who underwent gastrointestinal cancer surgery with prior SARS-CoV-2 infection between December 2022 and February 2023 were retrospectively reviewed. 174 cases underwent the same operation during December 2018 and February 2019 as control group. SARS-CoV-2-infected patients were further categorized into three groups based on infected time (1-3 weeks; 4-6 weeks; and ≥ 7 weeks). 90.3% of SARS-CoV-2-infected patients had mild symptoms. The COVID-19 vaccination rate was 71.0%, with a full vaccination rate of 48.4%. There were no significant differences in 30-day morbidity and mortality. There was also no significant difference in pulmonary complications, cardiovascular complications, and surgical complications between the three different diagnosis time groups. In conclusion, reducing waiting time for elective surgery was safe for gastrointestinal cancer patients in the context of an increased transmissibility and milder illness severity with Omicron variant.

Integration of machine learning for developing a prognostic signature related to programmed cell death in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) presents a significant global health burden, characterized by a heterogeneous molecular landscape and various genetic and epigenetic alterations. Programmed cell death (PCD) plays a critical role in CRC, offering potential targets for therapy by regulating cell elimination processes that can suppress tumor growth or trigger cancer cell resistance. Understanding the complex interplay between PCD mechanisms and CRC pathogenesis is crucial. This study aims to construct a PCD-related prognostic signature in CRC using machine learning integration, enhancing the precision of CRC prognosis prediction. METHOD: We retrieved expression data and clinical information from the Cancer Genome Atlas and Gene Expression Omnibus (GEO) datasets. Fifteen forms of PCD were identified, and corresponding gene sets were compiled. Machine learning algorithms, including Lasso, Ridge, Enet, StepCox, survivalSVM, CoxBoost, SuperPC, plsRcox, random survival forest (RSF), and gradient boosting machine, were integrated for model construction. The models were validated using six GEO datasets, and the programmed cell death score (PCDS) was established. Further, the model's effectiveness was compared with 109 transcriptome-based CRC prognostic models. RESULT: Our integrated model successfully identified differentially expressed PCD-related genes and stratified CRC samples into four subtypes with distinct prognostic implications. The optimal combination of machine learning models, RSF + Ridge, showed superior performance compared with traditional methods. The PCDS effectively stratified patients into high-risk and low-risk groups, with significant survival differences. Further analysis revealed the prognostic relevance of immune cell types and pathways associated with CRC subtypes. The model also identified hub genes and drug sensitivities relevant to CRC prognosis. CONCLUSION: The current study highlights the potential of integrating machine learning models to enhance the prediction of CRC prognosis. The developed prognostic signature, which is related to PCD, holds promise for personalized and effective therapeutic interventions in CRC.

HIF-2α-dependent TGFBI promotes ovarian cancer chemoresistance by activating PI3K/Akt pathway to inhibit apoptosis and facilitate DNA repair process.

Hypoxia-mediated chemoresistance plays a crucial role in the development of ovarian cancer (OC). However, the roles of hypoxia-related genes (HRGs) in chemoresistance and prognosis prediction and theirs underlying mechanisms remain to be further elucidated. We intended to identify and validate classifiers of hub HRGs for chemoresistance, diagnosis, prognosis as well as immune microenvironment of OC, and to explore the function of the most crucial HRG in the development of the malignant phenotypes. The RNA expression and clinical data of HRGs were systematically evaluated in OC training group. Univariate and multivariate Cox regression analysis were applied to construct hub HRGs classifiers for prognosis and diagnosis assessment. The relationship between classifiers and chemotherapy response and underlying pathways were detected by GSEA, CellMiner and CIBERSORT algorithm, respectively. OC cells were cultured under hypoxia or transfected with HIF-1α or HIF-2α plasmids, and the transcription levels of TGFBI were assessed by quantitative PCR. TGFBI was knocked down by siRNAs in OC cells, CCK8 and in vitro migration and invasion assays were performed to examine the changes in cell proliferation, motility and metastasis. The difference in TGFBI expression was examined between cisplatin-sensitive and -resistant cells, and the effects of TGFBI interference on cell apoptosis, DNA repair and key signaling molecules of cisplatin-resistant OC cells were explored. A total of 179 candidate HRGs were extracted and enrolled into univariate and multivariate Cox regression analysis. Six hub genes (TGFBI, CDKN1B, AKAP12, GPC1, TGM2 and ANGPTL4) were selected to create a HRGs prognosis classifier and four genes (TGFBI, AKAP12, GPC1 and TGM2) were selected to construct diagnosis classifiers. The HRGs prognosis classifier could precisely distinguish OC patients into high-risk and low-risk groups and estimate their clinical outcomes. Furthermore, the high-risk group had higher percentage of Macrophages M2 and exhibited higher expression of immunecheckpoints such as PD-L2. Additionally, the diagnosis classifiers could accurately distinguish OC from normal samples. TGFBI was further verified as a specific key target and demonstrated that its high expression was closely correlated with poor prognosis and chemoresistance of OC. Hypoxia upregulated the expression level of TGFBI. The hypoxia-induced factor HIF-2α but not HIF-1α could directly bind to the promoter region of TGFBI, and facilitate its transcription level. TGFBI was upregulated in cisplatin-sensitive and resistant ovarian cancer cells in a cisplatin time-dependent manner. TGFBI interference downregulated DNA repair-related markers (p-p95/NBS1, RAD51, p-DNA-PKcs, DNA Ligase IV and Artemis), apoptosis-related marker (BCL2) and PI3K/Akt pathway-related markers (PI3K-p110 and p-Akt) in cisplatin-resistant OC cells. In summary, the HRGs prognosis risk classifier could be served as a predictor for OC prognosis and efficacy evaluation. TGFBI, upregulated by HIF-2α as an HRG, promoted OC chemoresistance through activating PI3K/Akt pathway to reduce apoptosis and enhance DNA damage repair pathway.

Mechanism of Qili Qiangxin Capsule for Heart Failure Based on miR133a-Endoplasmic Reticulum Stress.

OBJECTIVE: To investigate the pharmacological mechanism of Qili Qiangxin Capsule (QLQX) improvement of heart failure (HF) based on miR133a-endoplasmic reticulum stress (ERS) pathway. METHODS: A left coronary artery ligation-induced HF after myocardial infarction model was used in this study. Rats were randomly assigned to the sham group, the model group, the QLQX group [0.32 g/(kg·d)], and the captopril group [2.25 mg/(kg·d)], 15 rats per group, followed by 4 weeks of medication. Cardiac function such as left ventricular ejection fraction (EF), fractional shortening (FS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), the maximal rate of increase of left ventricular pressure (+dp/dt max), and the maximal rate of decrease of left ventricular pressure (-dp/dt max) were monitored by echocardiography and hemodynamics. Hematoxylin and eosin (HE) and Masson stainings were used to visualize pathological changes in myocardial tissue. The mRNA expression of miR133a, glucose-regulated protein78 (GRP78), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), X-box binding protein1 (XBP1), C/EBP homologous protein (CHOP) and Caspase 12 were detected by RT-PCR. The protein expression of GRP78, p-IRE1/IRE1 ratio, cleaved-ATF6, XBP1-s (the spliced form of XBP1), CHOP and Caspase 12 were detected by Western blot. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to detect the rate of apoptosis. RESULTS: QLQX significantly improved cardiac function as evidenced by increased EF, FS, LVSP, +dp/dt max, -dp/dt max, and decreased LVEDP (P<0.05, P<0.01). HE staining showed that QLQX ameliorated cardiac pathologic damage to some extent. Masson staining indicated that QLQX significantly reduced collagen volume fraction in myocardial tissue (P<0.01). Results from RT-PCR and Western blot showed that QLQX significantly increased the expression of miR133a and inhibited the mRNA expressions of GRP78, IRE1, ATF6 and XBP1, as well as decreased the protein expressions of GRP78, cleaved-ATF6 and XBP1-s and decreased p-IRE1/IRE1 ratio (P<0.05, P<0.01). Further studies showed that QLQX significantly reduced the expression of CHOP and Caspase12, resulting in a significant reduction in apoptosis rate (P<0.05, P<0.01). CONCLUSION: The pharmacological mechanism of QLQX in improving HF is partly attributed to its regulatory effect on the miR133a-IRE1/XBP1 pathway.

Genetic susceptibility modifies the association of long-term air pollution exposure on Parkinson's disease.

Inconsistent findings exist regarding the potential association between polluted air and Parkinson's disease (PD), with unclear insights into the role of inherited sensitivity. This study sought to explore the potential link between various air pollutants and PD risk, investigating whether genetic susceptibility modulates these associations. The population-based study involved 312,009 initially PD-free participants with complete genotyping data. Annual mean concentrations of PM2.5, PM10, NO2, and NOx were estimated, and a polygenic risk score (PRS) was computed to assess individual genetic risks for PD. Cox proportional risk models were employed to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between ambient air pollutants, genetic risk, and incident PD. Over a median 12.07-year follow-up, 2356 PD cases (0.76%) were observed. Compared to the lowest quartile of air pollution, the highest quartiles of NO2 and PM10 pollution showed HRs and 95% CIs of 1.247 (1.089-1.427) and 1.201 (1.052-1.373) for PD incidence, respectively. Each 10 µg/m3 increase in NO2 and PM10 yielded elevated HRs and 95% CIs for PD of 1.089 (1.026-1.155) and 1.363 (1.043-1.782), respectively. Individuals with significant genetic and PM10 exposure risks had the highest PD development risk (HR: 2.748, 95% CI: 2.145-3.520). Similarly, those with substantial genetic and NO2 exposure risks were over twice as likely to develop PD compared to minimal-risk counterparts (HR: 2.414, 95% CI: 1.912-3.048). Findings suggest that exposure to air contaminants heightens PD risk, particularly in individuals genetically predisposed to high susceptibility.