Liver transplantation (LT) has become a standard treatment for end-stage liver diseases, and graft injury is intricately associated with poor prognosis. Granzyme B (GZMB) plays a vital role in natural killer (NK) cell biology, but whether NK-derived GZMB affects graft injury remains elusive. Through the analysis of single-cell RNA-sequencing data obtained from human LT grafts and the isolation of lymphocytes from mouse livers following ischemia-reperfusion injury (IRI), we demonstrated that 2NK cells with high expression of GZMB are enriched in patients and mice. Both systemically and liver-targeted depletion of NK cells led to a notable reduction in GZMB⁺ cell infiltration, subsequently resulting in diminished graft injury. Notably, the reconstitution of Il2rg ^-/- Rag2 ^-/- mice with purified Gzmb-KO NK cells demonstrated superior outcomes compared to those with wild-type NK cells. Crucially, global knockout of GZMB and pharmacological inhibition exhibited remarkable improvements in liver function in both mouse IRI and rat LT models. Moreover, a phosphorylated derivative of FDA-approved vidarabine was identified as an effective inhibitor of mouse GZMB activity by molecular dynamics, which could provide a potential avenue for therapeutic intervention. Therefore, targeting NK cell-derived GZMB during the LT process suggests potential therapeutic strategies to improve post-transplant outcomes.

Corticotomy is a clinical procedure to accelerate orthodontic tooth movement characterized by the regional acceleratory phenomenon (RAP). Despite its therapeutic effects, the surgical risk and unclear mechanism hamper the clinical application. Numerous evidences support macrophages as the key immune cells during bone remodeling. Our study discovered that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated bone remodeling in corticotomy by CX3CR1^CreERT2; R26^GFP lineage tracing system. Fluorescence staining, flow cytometry analysis, and western blot determined the significantly enhanced expression of binding immunoglobulin protein (BiP) and emphasized the activation of sensor activating transcription factor 6 (ATF6) in macrophages. Then, we verified that macrophage specific ATF6 deletion (ATF6^f/f; CX3CR1^CreERT2 mice) decreased the proportion of pro-inflammatory macrophages and therefore blocked the acceleration effect of corticotomy. In contrast, macrophage ATF6 overexpression exaggerated the acceleration of orthodontic tooth movement. In vitro experiments also proved that higher proportion of pro-inflammatory macrophages was positively correlated with higher expression of ATF6. At the mechanism level, RNA-seq and CUT&Tag analysis demonstrated that ATF6 modulated the macrophage-orchestrated inflammation through interacting with Tnfα promotor and augmenting its transcription. Additionally, molecular docking simulation and dual-luciferase reporter system indicated the possible binding sites outside of the traditional endoplasmic reticulum-stress response element (ERSE). Taken together, ATF6 may aggravate orthodontic bone remodeling by promoting Tnfα transcription in macrophages, suggesting that ATF6 may represent a promising therapeutic target for non-invasive accelerated orthodontics.
Animals ; Mice ; Macrophages/metabolism* ; Tumor Necrosis Factor-alpha/genetics* ; Tooth Movement Techniques/methods* ; Activating Transcription Factor 6/metabolism* ; Bone Remodeling ; Flow Cytometry ; Blotting, Western

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

This study retrospectively analyzed the clinical data of 43 patients with large-volume renal calculi treated with flexible ureteroscopic lithotripsy (FURL)at our hospital from August 2020 to August 2023. Among the patients, 26 were male and 17 were female; 22 had left-sided stones and 21 had right-sided stones. Thirty-three patients had preoperative placement of a double-J (D-J)stent, while 10 did not. The mean age was (42.7±11.1)years, the mean stone volume was (10.3±3.5)cm 3, and the mean operative time was (97.9±10.4)minutes. All procedures were completed using reusable flexible ureteroscopic lithotripsy. Twenty-two patients received traditional methods of stone expulsion after FURL (control group), while 21 patients received a combination of traditional methods and extracorporeal physical vibration lithotripsy (EPVL) after FURL (experimental group). The experimental group showed a significantly higher stone-free rate at one month (85.7% vs. 54.5%)and a lower reoperation rate (4.8% vs. 31.8%)compared to the control group. The difference in reoperation rates between the experimental and control groups was statistically significant ( P< 0.05). These results suggest that the combination of reusable ureteroscopic lithotripsy and EPVL is a feasible treatment option for large-volume renal calculi.

This study retrospectively analyzed the clinical data of 43 patients with large-volume renal calculi treated with flexible ureteroscopic lithotripsy (FURL)at our hospital from August 2020 to August 2023. Among the patients, 26 were male and 17 were female; 22 had left-sided stones and 21 had right-sided stones. Thirty-three patients had preoperative placement of a double-J (D-J)stent, while 10 did not. The mean age was (42.7±11.1)years, the mean stone volume was (10.3±3.5)cm 3, and the mean operative time was (97.9±10.4)minutes. All procedures were completed using reusable flexible ureteroscopic lithotripsy. Twenty-two patients received traditional methods of stone expulsion after FURL (control group), while 21 patients received a combination of traditional methods and extracorporeal physical vibration lithotripsy (EPVL) after FURL (experimental group). The experimental group showed a significantly higher stone-free rate at one month (85.7% vs. 54.5%)and a lower reoperation rate (4.8% vs. 31.8%)compared to the control group. The difference in reoperation rates between the experimental and control groups was statistically significant ( P< 0.05). These results suggest that the combination of reusable ureteroscopic lithotripsy and EPVL is a feasible treatment option for large-volume renal calculi.

With the increasing proportion of human papilloma virus(HPV)infection in the pathogenic factors of oro-pharyngeal cancer,a series of changes have occurred in the surgical treatment.While the treatment mode has been im-proved,there are still many problems,including the inconsistency between diagnosis and treatment modes,the lack of popularization of reconstruction technology,the imperfect post-treatment rehabilitation system,and the lack of effective preventive measures.Especially in terms of treatment mode for early oropharyngeal cancer,there is no unified conclu-sion whether it is surgery alone or radiotherapy alone,and whether robotic minimally invasive surgery has better func-tional protection than radiotherapy.For advanced oropharyngeal cancer,there is greater controversy over the treatment mode.It is still unclear whether to adopt a non-surgical treatment mode of synchronous chemoradiotherapy or induction chemotherapy combined with synchronous chemoradiotherapy,or a treatment mode of surgery combined with postopera-tive chemoradiotherapy.In order to standardize the surgical treatment of oropharyngeal cancer in China and clarify the indications for surgical treatment of oropharyngeal cancer,this expert consensus,based on the characteristics and treat-ment status of oropharyngeal cancer in China and combined with the international latest theories and practices,forms consensus opinions in multiple aspects of preoperative evaluation,surgical indication determination,primary tumor re-section,neck lymph node dissection,postoperative defect repair,postoperative complication management prognosis and follow-up of oropharyngeal cancer patients.The key points include:① Before the treatment of oropharyngeal cancer,the expression of P16 protein should be detected to clarify HPV status;② Perform enhanced magnetic resonance imaging of the maxillofacial region before surgery to evaluate the invasion of oropharyngeal cancer and guide precise surgical resec-tion of oropharyngeal cancer.Evaluating mouth opening and airway status is crucial for surgical approach decisions and postoperative risk prediction;③ For oropharyngeal cancer patients who have to undergo major surgery and cannot eat for one to two months,it is recommended to undergo percutaneous endoscopic gastrostomy before surgery to effectively improve their nutritional intake during treatment;④ Early-stage oropharyngeal cancer patients may opt for either sur-gery alone or radiation therapy alone.For intermediate and advanced stages,HPV-related oropharyngeal cancer general-ly prioritizes radiation therapy,with concurrent chemotherapy considered based on tumor staging.Surgical treatment is recommended as the first choice for HPV unrelated oropharyngeal squamous cell carcinoma(including primary and re-current)and recurrent HPV related oropharyngeal squamous cell carcinoma after radiotherapy and chemotherapy;⑤ For primary exogenous T1-2 oropharyngeal cancer,direct surgery through the oral approach or da Vinci robotic sur-gery is preferred.For T3-4 patients with advanced oropharyngeal cancer,it is recommended to use temporary mandibu-lectomy approach and lateral pharyngotomy approach for surgery as appropriate;⑥ For cT1-2N0 oropharyngeal cancer patients with tumor invasion depth＞3 mm and cT3-4N0 HPV unrelated oropharyngeal cancer patients,selective neck dissection of levels ⅠB to Ⅳ is recommended.For cN+HPV unrelated oropharyngeal cancer patients,therapeutic neck dissection in regions Ⅰ-Ⅴ is advised;⑦ If PET-CT scan at 12 or more weeks after completion of radiation shows intense FDG uptake in any node,or imaging suggests continuous enlargement of lymph nodes,the patient should undergo neck dissection;⑧ For patients with suspected extracapsular invasion preoperatively,lymph node dissection should include removal of surrounding muscle and adipose connective tissue;⑨ The reconstruction of oropharyngeal cancer defects should follow the principle of reconstruction steps,with priority given to adjacent flaps,followed by distal pedicled flaps,and finally free flaps.The anterolateral thigh flap with abundant tissue can be used as the preferred flap for large-scale postoperative defects.

Objective:To provide a basis for selecting the optimization method for intracavitary/interstitial brachytherapy (IC/ISBT) of cervical cancer by comparing graphical optimization (GO), inverse planning simulated annealing (IPSA), and hybrid inverse planning optimization (HIPO) using dosimetric and radiobiological models.Methods:This study selected 65 patients with cervical cancer who were treated with image-guided IC/ISBT. The afterloading therapy plans for these patients were optimized using GO, IPSA, and HIPO individually, with a prescription dose high-risk clinical target volume (HRCTV) D90 of 6 Gy. The non-parametric Friedman test and the non-parametric Wilcoxon rank test were employed to analyze the differences in duration, dose-volume parameters, and radiobiology between the three types of optimized plans. Results:Inverse planning optimization (IPSA: 46.53 s; HIPO: 98.36 s) took less time than GO (135.03 s). In terms of gross target volume (GTV) dose, the high-dose irradiation V150% (53.66%) was slightly higher in the HIPO-optimized plans, while the V200% (30.29%) was higher in the GO-optimized plans. The GO-optimized plans had a higher conformity index (CI; 0.91) than other plans, showing statistically significant differences. Compared with other plans, the HIPO-optimized plans showed the lowest doses of D1 cm 3 and D2 cm 3 at bladders and rectums and non-statistically significant doses at small intestines ( P > 0.05). In terms of the equivalent uniform biologically effective dose (EUBED) for HRCTV, the HIPO-optimized plans showed a higher value (12.35 Gy) than the GO-optimized plans (12.23 Gy) and the IPSA-optimized plans (12.13 Gy). Moreover, the EUBED at bladders was the lowest (2.38 Gy) in the GO-optimized plans, the EUBED at rectums was the lowest (3.74 Gy) in the HIPO-optimized plans, and the EUBED at small intestines was non-significantly different among the three types of optimized plans ( P = 0.055). There was no significant difference in the tumor control probability (TCP) predicted using the three types of optimized plans ( P > 0.05). The normal tissue complication probabilities (NTCPs) of bladders and rectums predicted using the HIPO-optimized plans were lower than those predicted using the GO- and IPSA-optimized plans( χ2 = 12.95-38.43, P < 0.01), and the NTCP of small intestines did not show significant differences ( P > 0.05). Conclusions:Among the three types of optimization algorithms, inverse optimization takes less time than GO. GO-optimized plans are more conformal than IPSA- and HIPO-optimized plans. HIPO-optimized plans can increase the biological coverage dose of the target volume and reduce the maximum physical/biological exposure and NTCP at bladders and rectums. Therefore, HIPO is recommended preferentially as an optimization algorithm for IC/ISBT for cervical cancer.

Objective:To establish a three-dimensional (3D) U-net-based deep learning model, and to predict the 3D dose distribution in CT-guided cervical cancer brachytherapy by using the established model.Methods:The brachytherapy plans of 114 cervical cancer cases with a prescription dose of 6 Gy for each case were studied. These cases were divided into training, validation, and testing groups, including 84, 11, and 19 patients, respectively. A total of 500 epochs of training were performed by using a 3D U-net model. Then, the dosimetric parameters of the testing groups were individually evaluated, including the mean dose deviation (MDD) and mean absolute dose deviation (MADD) at the voxel level, the Dice similarity coefficient (DSC) of the volumes enclosed by isodose surfaces, the conformal index (CI) of the prescription dose, the D90 and average dose Dmean delivered to high-risk clinical target volumes (HR-CTVs), and the D1 cm 3 and D2 cm 3 delivered to bladders, recta, intestines, and colons, respectively. Results:The overall MDD and MADD of the 3D dose matrix from 19 cases of the testing group were (-0.01 ± 0.03) and (0.04 ± 0.01) Gy, respectively. The CI of the prescription dose was 0.70 ± 0.04. The DSC of 50%-150% prescription dose was 0.89-0.94. The mean deviation of D90 and Dmean to HR-CTVs were 2.22% and -4.30%, respectively. The maximum deviations of the D1 cm 3 and D2 cm 3 to bladders, recta, intestines, and colons were 2.46% and 2.58%, respectively. The 3D U-net deep learning model took 2.5 s on average to predict a patient′s dose. Conclusions:In this study, a 3D U-net-based deep learning model for predicting 3D dose distribution in the treatment of cervical cancer was established, thus laying a foundation for the automatic design of cervical cancer brachytherapy.