The development of anticancer drugs to treat triple-negative breast cancer (TNBC) is an ongoing challenge. Immunogenic cell death (ICD) has garnered considerable interest worldwide as a promising synergistic modality for cancer chemoimmunotherapy. However, only few drugs or treatment modalities can trigger an ICD response and none of them exert a considerable clinical effect against TNBC. Therefore, new agents with potentially effective chemoimmunotherapeutic response are required. In this study, five new cyclometalated Ir(III) complexes containing isoquinoline alkaloid CˆN ligands were designed and synthesized. Among them, Ir-1 exhibited the highest in vitro cytotoxicity. Mechanistically, Ir-1 could trigger autophagy-dependent ferroptosis and a subsequent ferroptosis-dependent ICD response as well as indoleamine 2,3-dioxygenase (IDO) inhibition via reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress in MDA-MB-231 cells. When immunocompetent BALB/c mice were vaccinated with Ir-1-treated dying TNBC cells, antitumor CD8⁺ T-cell response and Foxp3⁺ T-cell depletion were induced, resulting in long-lasting antitumor immunity in TNBC cells. Moreover, combination therapy with Ir-1 and anti-PD1 could substantially augment in vivo therapeutic effects. Based on these results, Ir-1 is a promising candidate for chemoimmunotherapy against TNBC and its effects are mediated synergistically via ICD induction and IDO blockage.

[This corrects the article DOI: 10.1016/j.apsb.2018.08.009.].

Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

OBJECTIVE: Cigarette smoking exacerbates the progression of pulmonary tuberculosis (TB). The role of tertiary lymphoid structures (TLS) in chronic lung diseases has gained attention; however, it remains unclear whether smoking-exacerbated lung damage in TB is associated with TLS. This study aimed to analyze the characteristics of pulmonary TLS in smokers with TB and to explore the possible role of TLS in smoking-related lung injury in TB. METHODS: Lung tissues from 36 male patients (18 smokers and 18 non-smokers) who underwent surgical resection for pulmonary TB were included in this study. Pathological and immunohistological analyses were conducted to evaluate the quantity of TLS, and chest computed tomography (CT) was used to assess the severity of lung lesions. The correlation between the TLS quantity and TB lesion severity scores was analyzed. The immune cells and chemokines involved in TLS formation were also evaluated and compared between smokers and non-smokers. RESULTS: Smoker patients with TB had significantly higher TLS than non-smokers ( P < 0.001). The TLS quantity in both the lung parenchyma and peribronchial regions correlated with TB lesion severity on chest CT (parenchyma: r = 0.5767; peribronchial: r = 0.7373; both P < 0.001). Immunohistochemical analysis showed increased B cells, T cells, and C-X-C motif chemokine ligand 13 (CXCL13) expression in smoker patients with TB ( P < 0.001). CONCLUSION Smoker TB patients exhibited increased pulmonary TLS, which was associated with exacerbated lung lesions on chest CT, suggesting that cigarette smoking may exacerbate lung damage by promoting TLS formation.
Humans ; Male ; Tuberculosis, Pulmonary/immunology* ; Middle Aged ; Tertiary Lymphoid Structures/pathology* ; Adult ; Lung/pathology* ; Smoking/adverse effects* ; Smokers ; Aged ; Tomography, X-Ray Computed

Objective:To establish a three-dimensional finite element model of the nose, simulate and analyze the deformation of nasal tissue caused by different focal points, traction directions, and modes, provide the theoretical basis for the effectiveness of physical traction therapy, and guide the clinical selection of more efficient physical traction therapy methods.Methods:A finite element model of the nose was established by ANSYS Workbench 19.2 software based on image data obtained from CT scans of a 29-year-old male volunteer with normal nasal appearance in Peking University Third Hospital. Two focal points, the nasal tip, and the nasal columella, were selected, and three force directions, parallel to the forward, forward and down 30°, forward and down 60°, were applied. The deformation caused by different traction conditions on the skin, lining, and soft bone parts, as well as the four anatomical landmarks of the nasal tip, nasal root, the midpoint of the nasal columella, and the nasal base, were compared. The deformation produced by 10 minutes of continuous pulling and 10 times 1-minute pulse pulling were compared under the same pulling conditions. The deformations generated by two types of pulling modes within a 24-hour cycle: a single 1-hour cycle and 6 intermittent 10-minute cycles, were compared.Results:All traction conditions resulted in deformation of the nasal model, with the maximum deformation of the nasal tissue obtained by pulling forward and downward at 60° (4.632 9 mm) which was greater than other traction conditions (0.825 0-3.105 0 mm). The maximum deformation value was located near the nasion of the model’s skin layer. The deformation obtained by 10 minutes of continuous pulling (0.176 6 mm) was slightly greater than that obtained by 10 times of 1-minute pulse pulling (0.176 5 mm). Within 24 hours, the final deformation of multiple intermittent pulling modes (0.019 0 mm) was greater than that of a single pulling mode (0.004 3 mm).Conclusion:Physical traction can effectively deform the skin and soft tissue of the nose, and the most efficient operation is to continuously pinch the tip of the nose for a short period and apply tension parallel to the back of the nose downwards, repeating every a few hours.

Objective:To establish a three-dimensional finite element model of the nose, simulate and analyze the deformation of nasal tissue caused by different focal points, traction directions, and modes, provide the theoretical basis for the effectiveness of physical traction therapy, and guide the clinical selection of more efficient physical traction therapy methods.Methods:A finite element model of the nose was established by ANSYS Workbench 19.2 software based on image data obtained from CT scans of a 29-year-old male volunteer with normal nasal appearance in Peking University Third Hospital. Two focal points, the nasal tip, and the nasal columella, were selected, and three force directions, parallel to the forward, forward and down 30°, forward and down 60°, were applied. The deformation caused by different traction conditions on the skin, lining, and soft bone parts, as well as the four anatomical landmarks of the nasal tip, nasal root, the midpoint of the nasal columella, and the nasal base, were compared. The deformation produced by 10 minutes of continuous pulling and 10 times 1-minute pulse pulling were compared under the same pulling conditions. The deformations generated by two types of pulling modes within a 24-hour cycle: a single 1-hour cycle and 6 intermittent 10-minute cycles, were compared.Results:All traction conditions resulted in deformation of the nasal model, with the maximum deformation of the nasal tissue obtained by pulling forward and downward at 60° (4.632 9 mm) which was greater than other traction conditions (0.825 0-3.105 0 mm). The maximum deformation value was located near the nasion of the model’s skin layer. The deformation obtained by 10 minutes of continuous pulling (0.176 6 mm) was slightly greater than that obtained by 10 times of 1-minute pulse pulling (0.176 5 mm). Within 24 hours, the final deformation of multiple intermittent pulling modes (0.019 0 mm) was greater than that of a single pulling mode (0.004 3 mm).Conclusion:Physical traction can effectively deform the skin and soft tissue of the nose, and the most efficient operation is to continuously pinch the tip of the nose for a short period and apply tension parallel to the back of the nose downwards, repeating every a few hours.

Objective To measure the distance between the lateral compression Ⅱ(LC-Ⅱ)screw guide needle and the surrounding important structures around the anterior inferior iliac spine in pelvic fractures and to locate the needle point,so as to provide anatomical reference for clinical nail placement.Methods Totally 40 adult gross specimens of embalming were implanted with LC-Ⅱ screw guide needle under the surveillance of C-arm machine,and the specimens were dissected.The shortest distance between the insertion point and the lateral femoral cutaneous nerve,femoral nerve,femoral artery,femoral vein,anterior superior iliac spine and inguinal ligament was measured.The triangle was constructed between the insertion point,anterior superior iliac spine and inguinal ligament,and the exact location of the entry point was calculated.Results The average distance between the insertion point of the male needle and the femoral vein was(50.67±7.29)mm＞the anterior superior iliac spine(43.83±7.58)mm＞the femoral artery(38.35±6.63)mm＞the femoral nerve(31.17±1.67)mm=the inguinal ligament(28.69±6.59)mm＞the lateral femoral cutaneous nerve(7.98±3.81)mm.The mean distance between the insertion point of the female needle and the anterior superior iliac spine was(45.28±7.07)mm=femoral vein(43.72±6.89)mm＞femoral artery(33.76±6.33)mm＞femoral nerve(25.66±6.46)mm=inguinal ligament(23.22±5.00)mm＞lateral femoral cutaneous nerve(8.97±4.76)mm.The projection distance of the entry point was 31.77 mm for men and 38.41 mm for women.The Angle b was 42.81°for men and 31.71° for women.Conclusion The lateral femoral cutaneous nerve is most vulnerable to injury when LC-Ⅱ screw is inserted,and the risk of injury has nothing to do with sex.The insertion point positioning method a and b made LC-Ⅱ screw placement quickly,safely and accurately,and reduced fluoroscopy time and frequency.

Objective To investigate the diagnostic value Tamm-Horsfall protein(THP)and osteopontin(OPN)in serum and 24-hour urine for urolithiasis.Methods A total of 101 patients with urolithiasis who underwent flexible ureteroscopy lithotripsy at the Urology Department of Civil Aviation General Hospital from April 2020 to March 2023 were included as the stone group,and 50 healthy individuals were enrolled as the control group.The samples of serum and 24-hour urine samples were collected from both the groups,and the levels of THP and OPN were measured using enzyme-linked immunosorbent assay(ELISA).Logistic regression analysis was performed to evaluate the association between each biomarker and urolithiasis,and receiver operating characteristic(ROC)curves were plotted to assess their diagnostic value.Results The stone group showed significantly lower THP levels(20.13[13.12,26.03]mg/d)and OPN levels(51.24[36.72,101.37]μg/d)in 24-hour urine,and THP levels(182.01[160.91,209.20]ng/mL)and OPN lev-els(18.76[15.72,22.48]ng/mL)in serum compared to the control group(all the P＜0.001).Binary Logistic regression analysis re-vealed that THP(OR=0.736,95％CI:0.606-0.895),OPN(OR=0.975,95％CI:0.958-0.993)and citrate(OR=0.067,95％CI:0.012-0.376)in 24-hour urine,and THP(OR=0.946,95％CI:0.908-0.986)and OPN(OR=0.896,95％CI:0.803-0.999)in ser-um were the protective factors for urolithiasis,while calcium level(OR=2.125,95％CI:1.243-3.633)24-hour urine was a risk factor(all the P＜0.05).ROC curve analysis showed that the areas under the curve(AUCROC)for the individual diagnosis of urolithiasis were 0.846,0.809,0.786,0.823,0.748,and 0.755 for the above six biomarkers,respectively.The AUCROC for the combined diagnosis u-sing THP+OPN in serum,THP+OPN in 24-hour urine and all the six biomarkers were 0.882,0.920 and 0.984,respectively,indica-ting better diagnostic performance.Conclusion The combined detection of the THP and OPN levels in serum and 24-hour urine may have good diagnostic value for urolithiasis and serve as potential diagnostic biomarkers.

Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.