Background/Aims: Biliary tract cancer (BTC) frequently harbors KRAS mutations, which are associated with resistance to traditional treatment and a poor prognosis. Synthetic lethality (SL) strategy may provide other targets of KRAS. Therefore, we aim to identify and validate potential therapeutic targets of KRAS for the treatment of BTC via SL. Methods: The dependency (DepMap) projects were used to predict the synthetic lethal gene of KRAS. FDA-approved anticancer drug library was applied to screen potential drugs effective against KRAS-mutant BTC. Furthermore, the synthetic lethal effects or corresponding mechanisms of potential genes and drugs on BTC were investigated using KRAS-mutant and KRAS-wild type BTC cell lines, patient-derived xenografts (PDX), and KRAS oncogene-driven tumor models, as well as other KRAS-mutant cancer cell lines. Results: Initially, we discovered that the loss of GATA2 reduced the viability of KRAS-mutant but not KRAS-wild-type BTC. Subsequently, the drug library screened out disulfiram, which primarily exerts a synthetic lethal effect by inhibiting interleukin-1β (IL-1β) in KRAS-mutant BTC. Mechanistically, GATA2 specifically enhanced the transcription of IL-1β to promote NF-κB signaling in KRAS-mutant BTC. IL-1β inhibition phenocopied GATA2 deficiency, leading to reduced KRAS-mutant BTC viability. These synthetically lethal effects were confirmed using PDX, a KRAS oncogene-driven tumor model, as well as in other KRAS-mutant cancer cell lines. Conclusions In summary, these results indicate that inhibiting GATA2/IL1β could be a therapeutic strategy in KRAS-mutant BTC and potentially other cancers.

Background: Gestational diabetes mellitus (GDM) is a metabolic disorder posing significant risks to maternal and infant health, with a lack of effective early screening markers. Therefore, identifying early screening biomarkers for GDM with higher sensitivity and specificity is urgently needed. Methods: High-throughput sequencing was employed to screen for key circular RNAs (circRNAs), which were then evaluated using reverse transcription quantitative polymerase chain reaction. Logistic regression analysis was conducted to examine the relationship between clinical characteristics, circRNA expression, and adverse pregnancy outcomes. The diagnostic accuracy of circRNAs for early and mid-pregnancy GDM was assessed using receiver operating characteristic curves. Pearson correlation analysis was utilized to explore the relationship between circRNA levels and oral glucose tolerance test results. A predictive model for early GDM was established using logistic regression. Results: Significant alterations in circRNA expression profiles were detected in GDM patients, with hsa_circ_0031560 and hsa_ circ_0000793 notably upregulated during the first and second trimesters. These circRNAs were associated with adverse pregnancy outcomes and effectively differentiated GDM patients, with second trimester cohorts achieving an area under the curve (AUC) of 0.836. In first trimester cohorts, these circRNAs identified potential GDM patients with AUCs of 0.832 and 0.765, respectively. The early GDM prediction model achieved an AUC of 0.904, validated in two independent cohorts. Conclusion Hsa_circ_0031560, hsa_circ_0000793, and the developed model serve as biomarkers for early prediction or midterm diagnosis of GDM, offering clinical tools for early GDM screening.

Objective:To investigate the relationship between the quick sequential organ failure assessment (qSOFA) score, procalcitonin (PCT), blood lactate, hypersensitive C-reactive protein (hs-CRP) levels, and the prognosis of patients with severe acute pancreatitis (SAP).Methods:This retrospective analysis included 225 pancreatitis cases admitted to the Department of Gastroenterology at Ganzi Tibetan Autonomous Prefecture People's Hospital between February 2020 and February 2025. Patients were categorized into three groups based on severity: SAP group ( n=125), moderately severe acute pancreatitis (MSAP) group ( n=50), and mild acute pancreatitis (MAP) group ( n=50). General patient data, qSOFA scores, PCT, lactate, and hs-CRP levels were compared among the groups. Within the SAP group, patients were further divided into a favorable prognosis group ( n=101) and a poor prognosis group ( n=24) based on 28-day survival. The relationship between qSOFA score, PCT, lactate, hs-CRP, and SAP prognosis was analyzed. Normally distributed continuous data were expressed as Mean±SD. Independent samples t-test was used on comparison between two groups, while one-way ANOVA was used on comparison among multiple groups. LSD test was used on post-hoc pairwise comparison. Categorical data were expressed as n(%) and compared by χ2 test. Spearman correlation analysis assessed the correlation between qSOFA score, PCT, lactate, hs-CRP levels, and acute pancreatitis (AP) severity. Multivariable logistic regression modeling was used for joint prediction, incorporating qSOFA score, serum PCT, lactate, and hs-CRP levels to calculate combined predictive efficacy. The predictive performance of each indicator for prognosis was evaluated using receiver operating characteristic (ROC) curves. The areas under the ROC curves (AUC) were compared using DeLong's test. Results:Significant differences were observed among the MAP, MSAP, and SAP groups for qSOFA score [(0.63±0.29), (1.32±0.37), (1.70±0.33) points], serum PCT [(4.06±0.74), (5.35±0.89), (6.12±0.98) μg/L], lactate [(1.74±0.32), (2.77±0.70), (4.29±1.06) mmol/L], and hs-CRP levels [(15.38±3.75), (27.64±5.09), (35.26±6.42) mg/L] ( F values=187.51, 91.83, 169.18, 223.92, respectively, all P<0.001). The SAP group had significantly higher levels of qSOFA score, serum PCT, lactate, and hs-CRP compared to both the MAP and MSAP groups (all P<0.05), and the MSAP group levels were significantly higher than the MAP group (all P<0.05). The poor prognosis group had significantly higher levels of qSOFA score [(1.92±0.19) points], PCT [(6.65±0.47) μg/L], lactate [(5.14±0.62) mmol/L], and hs-CRP [(40.65±4.73) mg/L] compared to the favorable prognosis group [(1.65±0.25) points, (5.99±0.84) μg/L, (4.09±0.94) mmol/L, (34.16±6.09) mg/L] ( t values=4.96, 3.71, 5.20, 4.88, respectively, all P<0.001). Multivariate logistic regression analysis identified qSOFA score ( OR=14.658, 95% CI: 2.612-82.253), PCT ( OR=2.809, 95% CI: 1.288-6.129), lactate ( OR=3.658, 95% CI: 1.635-8.187), and hs-CRP ( OR=1.168, 95% CI: 1.055-1.293) as independent influencing factors for SAP patient prognosis ( P=0.002, 0.010, 0.002, 0.003, respectively). ROC curve analysis showed that the AUCs for qSOFA score, PCT, lactate, and hs-CRP in predicting poor prognosis in SAP patients were 0.754, 0.856, 0.766, and 0.809, with sensitivities of 87.50%, 83.33%, 83.33%, 85.50%, and specificities of 60.40%, 77.20%, 64.40%, 75.20%, respectively. The combined prediction model yielded an AUC of 0.934, with a sensitivity of 95.80% and specificity of 72.30%. Conclusion:The qSOFA score, PCT, blood lactate, and hs-CRP levels are associated with the severity of AP and possess reference value for predicting the prognosis of SAP patients.

Background: Gestational diabetes mellitus (GDM) is a metabolic disorder posing significant risks to maternal and infant health, with a lack of effective early screening markers. Therefore, identifying early screening biomarkers for GDM with higher sensitivity and specificity is urgently needed. Methods: High-throughput sequencing was employed to screen for key circular RNAs (circRNAs), which were then evaluated using reverse transcription quantitative polymerase chain reaction. Logistic regression analysis was conducted to examine the relationship between clinical characteristics, circRNA expression, and adverse pregnancy outcomes. The diagnostic accuracy of circRNAs for early and mid-pregnancy GDM was assessed using receiver operating characteristic curves. Pearson correlation analysis was utilized to explore the relationship between circRNA levels and oral glucose tolerance test results. A predictive model for early GDM was established using logistic regression. Results: Significant alterations in circRNA expression profiles were detected in GDM patients, with hsa_circ_0031560 and hsa_ circ_0000793 notably upregulated during the first and second trimesters. These circRNAs were associated with adverse pregnancy outcomes and effectively differentiated GDM patients, with second trimester cohorts achieving an area under the curve (AUC) of 0.836. In first trimester cohorts, these circRNAs identified potential GDM patients with AUCs of 0.832 and 0.765, respectively. The early GDM prediction model achieved an AUC of 0.904, validated in two independent cohorts. Conclusion Hsa_circ_0031560, hsa_circ_0000793, and the developed model serve as biomarkers for early prediction or midterm diagnosis of GDM, offering clinical tools for early GDM screening.

BACKGROUND: The proportion of patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is relatively high in China. However, these patients currently lack significant benefits from available neoadjuvant treatment options. This study aims to explore the potential application value of neoadjuvant targeted therapy by evaluating its efficacy and safety in patients with EGFR-mutant resectable lung adenocarcinoma. METHODS: A multicenter retrospective study was used to analyze the treatment effect of patients with stage IIA-IIIB EGFR-mutant lung adenocarcinoma who underwent surgical resection after receiving neoadjuvant targeted therapy from July 2019 to October 2024. RESULTS: A total of 24 patients with EGFR-mutant lung adenocarcinoma from three centers were included in this study. All patients successfully underwent surgery and achieved R0 resection of 100.0%. The objective response rate (ORR) was 83.3% (20/24) . The major pathologic response (MPR) rate was 37.5% (9/24), with 2 patients (8.3%) achieving pathological complete response (pCR). During neoadjuvant therapy, 13 out of 24 patients (54.2%) experienced adverse events of grade 1-2, with no occurrences of ≥ grade 3. The most common treatment-related adverse events were rash (n=4, 16.7%), mouth sores (n=2, 8.3%), and diarrhea (n=2, 8.3%). The median follow-up time was 33.0 months, no deaths occurred in all patients, and the overall survival (OS) rate was 100.0%. The 1-year disease-free survival (DFS) rate was 91.1%, and the 2-year DFS rate remained at 86.2%. CONCLUSIONS The application of neoadjuvant targeted therapy in patients with EGFR-mutant resectable lung adenocarcinoma is safe and feasible, and is expected to become a highly promising neoadjuvant treatment option for the patients with EGFR-mutant lung adenocarcinoma.
Humans ; ErbB Receptors/metabolism* ; Male ; Female ; Middle Aged ; Adenocarcinoma of Lung/surgery* ; Neoadjuvant Therapy ; Lung Neoplasms/surgery* ; Aged ; Retrospective Studies ; Mutation ; Adult

Real-time, noninvasive programmed death-ligand 1 (PD-L1) testing using molecular imaging has enhanced our understanding of the immune environments of neoplasms and has served as a guide for immunotherapy. However, the utilization of radiotracers in the imaging of human brain tumors using positron emission tomography/computed tomography (PET/CT) remains limited. This investigation involved the synthesis of [¹⁸F]AlF-NOTA-PCP2, which is a novel peptide-based radiolabeled tracer that targets PD-L1, and evaluated its imaging capabilities in orthotopic glioblastoma (GBM) models. Using this tracer, we could noninvasively monitor radiation-induced PD-L1 changes in GBM. [¹⁸F]AlF-NOTA-PCP2 exhibited high radiochemical purity (>95%) and stability up to 4 h after synthesis. It demonstrated specific, high-affinity binding to PD-L1 in vitro and in vivo, with a dissociation constant of 0.24 nM. PET/CT imaging, integrated with contrast-enhanced magnetic resonance imaging, revealed significant accumulation of [¹⁸F]AlF-NOTA-PCP2 in orthotopic tumors, correlating with blood-brain barrier disruption. After radiotherapy (15 Gy), [¹⁸F]AlF-NOTA-PCP2 uptake in tumors increased from 9.51% ± 0.73% to 12.04% ± 1.43%, indicating enhanced PD-L1 expression consistent with immunohistochemistry findings. Fractionated radiation (5 Gy × 3) further amplified PD-L1 upregulation (13.9% ± 1.54% ID/cc) compared with a single dose (11.48% ± 1.05% ID/cc). Taken together, [¹⁸F]AlF-NOTA-PCP2 may be a valuable tool for noninvasively monitoring PD-L1 expression in brain tumors after radiotherapy.

Objective To establish a rat model of acclimatization to motion sickness(MS)induced by rotational stimulation.Methods To determine the stimulation conditions of MS,SD rats were divided into a static control group(SCG)and a single rotation stimulation group(SRG)before being subjected to the motion sickness index(MSI)measurement,open-field experiment and Morris water maze experiment after rotational stimulation to verify the feasibility of MS being induced in rats.Morris water maze experiments were performed to find out whether rotational stimulation could be used to induce MS in rats.During experiments on acclimatization,the SD rats were divided into the control group(Ctrl),one day of rotational stimulation group(Day1),three days of continuous rotational stimulation group(Day3),and seven days of continuous rotational stimulation group(Day7)before the changes in the MSI and behavior of these rats were recorded so as to explore the relationship between continuous stimulation and MS acclimatization in rats.Results After rotational stimulation,the rats showed a significant increase in the number of fecal pellets(P<0.0001)and in the MSI(P<0.0001)compared with the SCG.In the open field experiment,the rats showed a significant decrease in the spontaneous activity time(AT)(P<0.0001),total spontaneous activity distance(TD)(P<0.001)and distance moved by the center point per second(DMCPS)(P<0.001).The time taken to climb onto the platform(latency to find the platform,LP)(P<0.0001)and the total distance to the platform(distance to the platform,DP)(P<0.001)were significantly increased during the Morris water maze experiment.Acclimatization experiments revealed a significant increase in MSI and in the number of fecal pellets in the Day1 and Day3 groups of rotational stimulation compared to the Ctrl group(P<0.0001).AT(P<0.01),TD(P<0.05)and DMCPS(P<0.01)were significantly decreased,while LP and DP were significantly increased(P<0.0001),but there was no statistically significant difference in indices compared with the Day7 group(P>0.05).Conclusion Sinusoidal stimulation can induce MS in rats,and twice-a-day,continuous rotational stimulation for seven days can lead to acclimatization.The rat MS model can be assessed via behavioral experiments.

Real-time,noninvasive programmed death-ligand 1(PD-L1)testing using molecular imaging has enhanced our understanding of the immune environments of neoplasms and has served as a guide for immunotherapy.However,the utilization of radiotracers in the imaging of human brain tumors using positron emission tomography/computed tomography(PET/CT)remains limited.This investigation involved the synthesis of[18F]AlF-NOTA-PCP2,which is a novel peptide-based radiolabeled tracer that targets PD-L1,and evaluated its imaging capabilities in orthotopic glioblastoma(GBM)models.Using this tracer,we could noninvasively monitor radiation-induced PD-L1 changes in GBM.[18F]AlF-NOTA-PCP2 exhibited high radiochemical purity(＞95％)and stability up to 4 h after synthesis.It demonstrated specific,high-affinity binding to PD-L1 in vitro and in vivo,with a dissociation constant of 0.24 nM.PET/CT imaging,integrated with contrast-enhanced magnetic resonance imaging,revealed significant accumulation of[18F]AlF-NOTA-PCP2 in orthotopic tumors,correlating with blood-brain barrier disruption.After radiotherapy(15 Gy),[18F]AlF-NOTA-PCP2 uptake in tumors increased from 9.51％±0.73％to 12.04％±1.43％,indicating enhanced PD-L1 expression consistent with immunohisto-chemistry findings.Fractionated radiation(5 Gy × 3)further amplified PD-L1 upregulation(13.9％±1.54％ID/cc)compared with a single dose(11.48％±1.05％ID/cc).Taken together,[18F]AlF-NOTA-PCP2 may be a valuable tool for noninvasively monitoring PD-L1 expression in brain tumors after radiotherapy.

[Objective] To analyze the influencing factors of repeat blood donor lapsing using a zero-inflated poisson regression model (ZIP). [Methods] The blood donation behavior of 12 498 whole blood donors from 2020 was tracked until December 31, 2023. The factors influencing the frequency of blood donations in a given year was analyzed using ZIP, and donors with 0 blood donation in that year were considered to have lapsed. The changes in relevant influencing factors associated with each blood donation were measured and modeled for analysis. [Results] The zero-inflated part of ZIP showed that the risk of lapsing of male blood donors was 2.24 times that of female blood donors (OR 95% CI:1.864-2.696, P<0.001); the risk of lapsing of the 35-44 age group and over 45 age group was respectively 40% (OR 95% CI:0.455-0.790, P<0.001) and 61%(OR 95% CI:0.268-0.578, P<0.001) lower than that of the under 25 age group; the risk of lapsing for those who have donated blood twice and ≥3 times was respectively 50% (OR 95% CI:0.405-0.609, P<0.001) and 81% (OR 95% CI:0.154-0.225, P<0.001) lower than that of first-time donors; the risk of lapsing of those with junior high or high school education was 1.2 times that of those with a college degree or higher (OR 95% CI:1.033-1.384, P<0.05); the risk of lapsing for the divorced group was 2.02 times that of the married group (OR 95% CI:1.445-2.820, P<0.001); the risk of lapsing for those with an income (Yuan) of 10 000 to 50 000, 50 000 to 100 000 and more than 100 000 was respectively 0.67 (OR 95% CI:0.552-0.818, P<0.001), 0.72 (OR 95% CI:0.591-0.884, P=0.002) and 0.67 (OR 95% CI:0.535-0.834, P<0.001) times that of those with an income (Yuan) of less than 10 000. The results of the Poisson part are consistent with the results of the zero-inflated part in terms of age and education level. [Conclusion] Blood donor lapsing is overall related to factors such as gender, age, donation frequency, education, marital status and family income. It's essential to care for those blood donors prone to lapse to retain more regular blood donors.

Background: Gestational diabetes mellitus (GDM) is a metabolic disorder posing significant risks to maternal and infant health, with a lack of effective early screening markers. Therefore, identifying early screening biomarkers for GDM with higher sensitivity and specificity is urgently needed. Methods: High-throughput sequencing was employed to screen for key circular RNAs (circRNAs), which were then evaluated using reverse transcription quantitative polymerase chain reaction. Logistic regression analysis was conducted to examine the relationship between clinical characteristics, circRNA expression, and adverse pregnancy outcomes. The diagnostic accuracy of circRNAs for early and mid-pregnancy GDM was assessed using receiver operating characteristic curves. Pearson correlation analysis was utilized to explore the relationship between circRNA levels and oral glucose tolerance test results. A predictive model for early GDM was established using logistic regression. Results: Significant alterations in circRNA expression profiles were detected in GDM patients, with hsa_circ_0031560 and hsa_ circ_0000793 notably upregulated during the first and second trimesters. These circRNAs were associated with adverse pregnancy outcomes and effectively differentiated GDM patients, with second trimester cohorts achieving an area under the curve (AUC) of 0.836. In first trimester cohorts, these circRNAs identified potential GDM patients with AUCs of 0.832 and 0.765, respectively. The early GDM prediction model achieved an AUC of 0.904, validated in two independent cohorts. Conclusion Hsa_circ_0031560, hsa_circ_0000793, and the developed model serve as biomarkers for early prediction or midterm diagnosis of GDM, offering clinical tools for early GDM screening.