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.

Objective:To investigate the regulatory effects of transcutaneous auricular vagus nerve stimulation (taVNS) on functional connectivity (FC) of thalamic subregions in patients with premenstrual syndrome (PMS).Methods:This study was a cross-sectional investigation. Clinical, laboratory, and imaging data were retrospectively collected from 56 PMS patients (PMS group) and 66 healthy controls (control group) recruited from various universities and hospitals in Nanning between November 2021 and June 2024. Resting-state functional MRI (fMRI) data and fMRI data during taVNS immediate stimulation (2 Hz, 25 Hz) were acquired from subjects during their late luteal phase. Using thalamic subregions (anterior thalamic nucleus, lateral nucleus, ventral nucleus, medial nucleus, central nucleus, posterior nucleus) as seeds, two-sample t-tests or paired t-tests were employed to analyze alterations in thalamic subregion FC in PMS patients and the regulatory effects of taVNS on these changes. Independent samples t-test were used to compare the differences in clinical and laboratory indicators between the PMS group and the control group. The relationship between taVNS regulation of thalamic subregion FC in PMS patients and thalamic internal functional connectivity were analyzed using mediation effect analysis. Results:Compared to the control group, patients in the PMS group showed increased scores on the Daily Record of Severity of Problems, Pittsburgh Sleep Quality Index, Self-Rating Anxiety Scale, Self-Rating Depression Scale, Hamilton Anxiety Rating Scale 17, and Hamilton Depression Rating Scale 14 during the late luteal phase ( P<0.05). At baseline, PMS patients exhibited higher FC between the left thalamic lateral nucleus and the left insula, and lower FC between the left medial nucleus, posterior nucleus, and ventral nucleus of the thalamus and the right middle frontal gyrus (MFG) compared to the control group (GRF corrected, voxel-level P<0.001, cluster-level P<0.05). During 2 Hz taVNS immediate stimulation in PMS group, FC between the left thalamic medial nucleus, posterior nucleus, ventral nucleus and the right MFG, as well as the FC between the left thalamic ventral nucleu and the left MFG increased compared to baseline levels; meanwhile, FC between the left thalamic posterior nucleus, ventral nucleus and the left insula decreased compared to baseline levels (GRF corrected, voxel-level P<0.001, cluster-level P<0.05). During 25 Hz taVNS immediate stimulation, the FC between the left thalamic ventral nucleus and the right MFG decreased compared to the baseline level (GRF corrected, voxel-level P<0.001, cluster-level P<0.05). Mediation effect analysis showed that the FC between the left thalamic posterior nucleus and the left lateral nucleus mediated part of the association between the FC of the left lateral thalamic nucleus-left insula and the FC of the left ventral thalamic nucleus-left putamen/insula; there were significant direct effects between the FC of the left lateral thalamic nucleus-the left posterior nucleus and FC of the left lateral thalamic nucleus-the left insula, as well as between the FC of the left ventral thalamic nucleus-the left MFG and FC of the left ventral thalamic nucleus-the right MFG. Conclusions:taVNS can modulate abnormal FC of the left thalamic subregions in PMS patients, restoring it toward normalization. The regulatory effects of 2 Hz stimulation are more pronounced than those of 25 Hz stimulation. This modulation primarily operates through two pathways: the left thalamic lateral nucleus-left insula-left thalamic ventral nucleus pathway and the left MFG-left thalamic ventral nucleus-right MFG.

Objective:To investigate the regulatory effects of transcutaneous auricular vagus nerve stimulation (taVNS) on functional connectivity (FC) of thalamic subregions in patients with premenstrual syndrome (PMS).Methods:This study was a cross-sectional investigation. Clinical, laboratory, and imaging data were retrospectively collected from 56 PMS patients (PMS group) and 66 healthy controls (control group) recruited from various universities and hospitals in Nanning between November 2021 and June 2024. Resting-state functional MRI (fMRI) data and fMRI data during taVNS immediate stimulation (2 Hz, 25 Hz) were acquired from subjects during their late luteal phase. Using thalamic subregions (anterior thalamic nucleus, lateral nucleus, ventral nucleus, medial nucleus, central nucleus, posterior nucleus) as seeds, two-sample t-tests or paired t-tests were employed to analyze alterations in thalamic subregion FC in PMS patients and the regulatory effects of taVNS on these changes. Independent samples t-test were used to compare the differences in clinical and laboratory indicators between the PMS group and the control group. The relationship between taVNS regulation of thalamic subregion FC in PMS patients and thalamic internal functional connectivity were analyzed using mediation effect analysis. Results:Compared to the control group, patients in the PMS group showed increased scores on the Daily Record of Severity of Problems, Pittsburgh Sleep Quality Index, Self-Rating Anxiety Scale, Self-Rating Depression Scale, Hamilton Anxiety Rating Scale 17, and Hamilton Depression Rating Scale 14 during the late luteal phase ( P<0.05). At baseline, PMS patients exhibited higher FC between the left thalamic lateral nucleus and the left insula, and lower FC between the left medial nucleus, posterior nucleus, and ventral nucleus of the thalamus and the right middle frontal gyrus (MFG) compared to the control group (GRF corrected, voxel-level P<0.001, cluster-level P<0.05). During 2 Hz taVNS immediate stimulation in PMS group, FC between the left thalamic medial nucleus, posterior nucleus, ventral nucleus and the right MFG, as well as the FC between the left thalamic ventral nucleu and the left MFG increased compared to baseline levels; meanwhile, FC between the left thalamic posterior nucleus, ventral nucleus and the left insula decreased compared to baseline levels (GRF corrected, voxel-level P<0.001, cluster-level P<0.05). During 25 Hz taVNS immediate stimulation, the FC between the left thalamic ventral nucleus and the right MFG decreased compared to the baseline level (GRF corrected, voxel-level P<0.001, cluster-level P<0.05). Mediation effect analysis showed that the FC between the left thalamic posterior nucleus and the left lateral nucleus mediated part of the association between the FC of the left lateral thalamic nucleus-left insula and the FC of the left ventral thalamic nucleus-left putamen/insula; there were significant direct effects between the FC of the left lateral thalamic nucleus-the left posterior nucleus and FC of the left lateral thalamic nucleus-the left insula, as well as between the FC of the left ventral thalamic nucleus-the left MFG and FC of the left ventral thalamic nucleus-the right MFG. Conclusions:taVNS can modulate abnormal FC of the left thalamic subregions in PMS patients, restoring it toward normalization. The regulatory effects of 2 Hz stimulation are more pronounced than those of 25 Hz stimulation. This modulation primarily operates through two pathways: the left thalamic lateral nucleus-left insula-left thalamic ventral nucleus pathway and the left MFG-left thalamic ventral nucleus-right MFG.

Objective:To investigate the role of miRNA-4298/PADI4/p53 signal axis in mediating 4f-induced apoptosis of leukemia cells.Methods:The cell growth density was observed under inverted microscope and the proliferation of leukemia cells was detected by CCK-8 counting assay. The expression of PADI4 and P53 at mRNA level was detected by qRT-PCR. Cell cycle and apoptosis were measured with flow cytometry. The expression of PADI4, P53, Bcl-2, Bax, caspase-3 and caspase-9 at protein level was detected by Western blot. Differential miRNA and mRNA expression profiles was detected by next generation sequencing. Databases such as TargetScan were used to predict the potential upstream and downstream genes of PADI4. A luciferase reporter assay was used to detect the 3′UTR of PADI4 targeted by miRNA-4298. Cell transfection assay was used to detect the effect siRNA, PADI4 vector, miRNA mimics and miRNA inhibitor in interference and rescue.Results:Nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor 4f could inhibit the proliferation of THP-1, K562 and U937 cells, and induce the apoptosis of these leukemia cells. It downregulated the expression of PADI4 mainly through the binding activity of miRNA-4298 to miRNA sponges, which resulted in the proliferation inhibition and apoptosis of leukemia cells. The inhibited proliferation and apoptosis of leukemia cells by 4f were associated with the increase of P53 expression after the decrease of PADI4 expression. The PADI4-dependent upregulation of P53 led to the ratio inversion of downstream Bcl-2/Bax, which activated caspase-3 or caspase-9 to induce the apoptosis of leukemia cells.Conclusions:The apoptosis of leukemia cells induced by Nrf2 inhibitor 4f was mainly associated with the miRNA-4298/PADI4/p53 axis, suggesting that it might be a novel signaling pathway for targeted therapy.

Objective:To preliminarily evaluate the myocardium of pilots by noninvasive and radiation free cardiac MRI mapping technology, and to explore its application value in evaluating the myocardium of pilots.Methods:Case-control study was adopted in this study. Pilots and normal personnel who had cardiac MRI in Air Force Medical Center from October of 2020 to July of 2022 were selected, and they were divided into 20-40 years group and >40 years group. The differences of myocardial longitudinal relaxation time T1, transverse relaxation time T2 and T2 * values between pilots and normal personnel at different ages were analyzed and compared. Pilots were divided into groups according to flying hours and aircraft types, and the differences of myocardial T1, T2 and T2 * values among pilots in different flying hours and aircraft types were analyzed and compared. Results:The average myocardial T1 value of pilots [(1 011.18±24.70) ms] was lower than that of normal personnel [(1 025.07±25.74) ms], and the difference was significant ( t=2.10, P=0.040). The myocardial T1 value of pilots >40 years old [(1 006.04±29.15)ms] was lower than that of normal personnel [(1 029.68±20.24) ms], and the difference was significant ( t=2.30, P=0.032). The myocardial T1 value of fighter pilots [(999.04±17.39)ms] was lower than that of the bomber, transporter, helicopter pilots [(1 023.33±25.53) ms], and the difference was significant ( t=2.73, P=0.012). There was no significant difference in myocardial T1, T2 and T2 * values between pilots and nornal personnel aged 20-40 years old; there was no significant difference in T2 and T2 * values between pilots and normal personnel in the age group of >40 years old (all P>0.05). There was also no significant difference in myocardial T1, T2 and T2 * values among the pilots in different flying hours (all P>0.05). Conclusions:The level of cardiomyocyte hypertrophy or myocardial fibrosis in fighter pilots might be lower than that in other aircraft types pilots. Cardiac MRI mapping has potential value in evaluating the myocardium of pilots.

Objective:To preliminarily evaluate the myocardium of pilots by noninvasive and radiation free cardiac MRI mapping technology, and to explore its application value in evaluating the myocardium of pilots.Methods:Case-control study was adopted in this study. Pilots and normal personnel who had cardiac MRI in Air Force Medical Center from October of 2020 to July of 2022 were selected, and they were divided into 20-40 years group and >40 years group. The differences of myocardial longitudinal relaxation time T1, transverse relaxation time T2 and T2 * values between pilots and normal personnel at different ages were analyzed and compared. Pilots were divided into groups according to flying hours and aircraft types, and the differences of myocardial T1, T2 and T2 * values among pilots in different flying hours and aircraft types were analyzed and compared. Results:The average myocardial T1 value of pilots [(1 011.18±24.70) ms] was lower than that of normal personnel [(1 025.07±25.74) ms], and the difference was significant ( t=2.10, P=0.040). The myocardial T1 value of pilots >40 years old [(1 006.04±29.15)ms] was lower than that of normal personnel [(1 029.68±20.24) ms], and the difference was significant ( t=2.30, P=0.032). The myocardial T1 value of fighter pilots [(999.04±17.39)ms] was lower than that of the bomber, transporter, helicopter pilots [(1 023.33±25.53) ms], and the difference was significant ( t=2.73, P=0.012). There was no significant difference in myocardial T1, T2 and T2 * values between pilots and nornal personnel aged 20-40 years old; there was no significant difference in T2 and T2 * values between pilots and normal personnel in the age group of >40 years old (all P>0.05). There was also no significant difference in myocardial T1, T2 and T2 * values among the pilots in different flying hours (all P>0.05). Conclusions:The level of cardiomyocyte hypertrophy or myocardial fibrosis in fighter pilots might be lower than that in other aircraft types pilots. Cardiac MRI mapping has potential value in evaluating the myocardium of pilots.

Objective To propose an accurate method of noninvasive determination of central venous pressure(CVP ) by locating the central point of right atrium (RA ) using echocardiography .Methods Through the 3D reconstruction ,the accurate positions of RA of 30 patients who had been examined by multislice 3‐dimensional computed tomography for chest imaging were recorded .Based on solid geometric principles ,the central point in RA was located by echocardiography and then compared with CT‐location point .The accuracy and feasibility were assessed by absolute distance (Da) ,vertical distance (Dv) and the whole time of location (T) between the two points .Results Mean Da ,Dv and T of the whole subjects were 07.6cm(95% CI:06.2to08.1cm),01.6cm(95% CI:-00.2to03.4cm),and438.0s(95% CI:400.1to 47 4.0 s) ,respectively .Conclusions The echocardiographic method on the basis of solid geometry proposed in this study could be used to locate the central point in RA accurately and simply .Thus it would be helpful to improve the accuracy of noninvasive determination of central venous pressure .

Objective To investigate the remineralizing therapy of deep caries and in vitro biomimetic remineralization of demineralized dentin by phosphorylated chitosan/amorphous calcium phosphate compound (P-chi/ACP) and tripolyphosphate (TPP). Methods Thirty-two extracted human molars were cut and completely demineralized. Two samples were used to show the characteristics by transmission electron microscopy (TEM). The other 30 samples were divided into two groups:fifteen samples were treated by P-chi/ACP and TPP (P-chi/ACP+TPP group), the other fifteen samples were not treated by TPP (P-chi/ACP group). All of the samples were distinguished into experimental side and control side, and then they were set on the in vitro model for 1 week. Micro-computed tomography (μCT) and TEM were used to assess the effects of remineralization. Results μCT detection revealed that the mineral density were higher in the experimental sides (125.42±12.16 and 119.39±8.64) than that of control sides (96.96±10.56 and 105.27±9.42) in both groups (P＜0.01). TEM figures showed that hierarchical intrafibrillar remineralization was realized in samples of P-chi/ACP+TPP group, while trace amounts of hierarchical remineralization was detected in P-chi/ACP group. Conclusion Fully demineralized dentin appears to have the potential to be remineralized with the application of P-chi/ACP. The ultrastructure of samples is better in P-chi/ACP+TPP group than that of P-chi/ACP group.