Transalveolar technique for sinus floor elevation(TSFE)offers the advantages of minimal invasiveness,reduced postoperative reaction,and shorter operative time for vertical bone augmentation in the maxillary posterior region.The clinical data of one patient with severe deficiency of residual bone height(RBH)in the maxillary posterior region,a blood vessel visible in the lateral wall of the maxillary sinus and a visible septum at the floor of the maxillary sinus were reported,and two-stage flexible TSFE was used to improve the vertical bone height of the operated area while reducing trauma,the risk of Schneiderian membrane rupture and maxillary sinus infection,etc.,and the relevant literatures were reviewed.The patient,male,26 years old,complained of missing left maxillary posterior teeth for more than 1 year and requested restoration.The patient had 27 missing teeth,normal keratinized gingiva,full alveolar ridge,no elongation of the opposing teeth,fair width of the proximal and normal occlusal distance.The results of cone beam CT(CBCT)showed that the distance between the sinus crests at the site of the 27 teeth was about 3 mm,the width of the alveolar bone was about 12.8 mm,the bone density was normal,and there were no residual roots or other abnormalities;no cyst-like lesions were seen in the walls of the maxillary sinuses bilaterally,and separation was seen at the floor of the maxillary sinus on the left side and a blood vessel was seen in the lateral wall of the maxillary sinus.A diagnosis of Kennedy class Ⅱ maxillary tooth defects was made.After two stages of TSFE,the Schneiderian membrane was intact and the bone height of the implant area was elevated to 9.6 mm from 3 mm preoperatively after the completion of the restoration,with stable bone augmentation,good osseointegration,and restoration of normal occlusal function.For the patients with severe bone height deficiency in the maxillary posterior region,flexible two-stage TSFE should be considered,which can help to reduce the risk of maxillary sinus infection and Schneiderian membrane rupture while minimizing the damage and obtaining the ideal bone augmentation results.

Cancer is one of the major diseases of high morbidity and mortality worldwide,and its therapeutic approaches are facing great challenges.Immunotherapy,especially the activation of innate immunity represented by the cGAS-STING signaling pathway,is the current research hotspot in tumor immunotherapy.Activation of innate immune response by gas therapy is the latest development in tumor therapeutic approaches,especially the use of gas signaling molecules(NOx CO,H2S and SO2)to activate the cGAS-STING signaling pathway to induce intrinsic immunity of the organism,which leads to anti-tumor immunotherapy.Although intrinsic immunity activated by gas signaling molecules plays an important role in tumor immunotherapy,few reviews have been reported on its association with the cGAS-STING signaling mechanism.In this paper,we will comprehensively describe how gas signaling molecules damage the mitochondrial matrix and DNA damage through oxidative/nitrosative stress,thereby activating the cGAS-STING signaling pathway and triggering the innate immune cascade,aiming to summarize the process of activation of anti-tumor immune effects by gas signaling molecules,and to provide more references for the gas therapies in the future anti-tumor immunity research.

Breast cancer is the leading cause of cancer-related mortality among women worldwide and has drawn extensive research attention.Owing to its molecular heterogeneity,drug resistance,and low therapeutic response,single-modality treatments often fail to achieve satisfactory efficacy or broad applicability.Combination therapy,designed based on the pathophysiological characteristics,related signaling pathways,and biomarkers of breast cancer,has emerged as a promising approach for improving therapeutic outcomes.With the advancement of research on combination strategies,the understanding of their molecular mechanisms—particularly key signaling pathways and biomarkers—has become increasingly important.However,comprehensive reviews addressing these molecular mechanisms and synergistic strategies remain scarce.This article summarizes recent advances in combination therapy for breast cancer,providing a comprehensive review of recent combination therapies for breast cancer and their underlying molecular mechanisms,and focusing on key signaling pathways involved in combination therapy and synergistic strategies,thereby providing theoretical insights and reference for researchers,graduate students,and clinicians engaged in the development of novel combination therapeutic strategies for breast cancer and related malignancies.

Cancer is one of the major diseases of high morbidity and mortality worldwide,and its therapeutic approaches are facing great challenges.Immunotherapy,especially the activation of innate immunity represented by the cGAS-STING signaling pathway,is the current research hotspot in tumor immunotherapy.Activation of innate immune response by gas therapy is the latest development in tumor therapeutic approaches,especially the use of gas signaling molecules(NOx CO,H2S and SO2)to activate the cGAS-STING signaling pathway to induce intrinsic immunity of the organism,which leads to anti-tumor immunotherapy.Although intrinsic immunity activated by gas signaling molecules plays an important role in tumor immunotherapy,few reviews have been reported on its association with the cGAS-STING signaling mechanism.In this paper,we will comprehensively describe how gas signaling molecules damage the mitochondrial matrix and DNA damage through oxidative/nitrosative stress,thereby activating the cGAS-STING signaling pathway and triggering the innate immune cascade,aiming to summarize the process of activation of anti-tumor immune effects by gas signaling molecules,and to provide more references for the gas therapies in the future anti-tumor immunity research.

Breast cancer is the leading cause of cancer-related mortality among women worldwide and has drawn extensive research attention.Owing to its molecular heterogeneity,drug resistance,and low therapeutic response,single-modality treatments often fail to achieve satisfactory efficacy or broad applicability.Combination therapy,designed based on the pathophysiological characteristics,related signaling pathways,and biomarkers of breast cancer,has emerged as a promising approach for improving therapeutic outcomes.With the advancement of research on combination strategies,the understanding of their molecular mechanisms—particularly key signaling pathways and biomarkers—has become increasingly important.However,comprehensive reviews addressing these molecular mechanisms and synergistic strategies remain scarce.This article summarizes recent advances in combination therapy for breast cancer,providing a comprehensive review of recent combination therapies for breast cancer and their underlying molecular mechanisms,and focusing on key signaling pathways involved in combination therapy and synergistic strategies,thereby providing theoretical insights and reference for researchers,graduate students,and clinicians engaged in the development of novel combination therapeutic strategies for breast cancer and related malignancies.

Objective:To investigate the change of collagen fibers in locally recurrent esophageal squamous cell carcinoma after radical chemoradiotherapy and the discrepancy of adverse effects and survival outcomes among groups with different salvage treatments, provide references for the options of salvage therapy.Methods:Medical records of 137 patients with esophageal squamous cell carcinoma who received radical chemoradiotherapy and had local recurrence admitted to Cancer Center of Renmin Hospital of Wuhan University from January 2015 to September 2022 were retrospectively collected. The expression of collagen fibers in paraffin samples of cases with different recurrence time was determined by Masson staining, and the differences of the average optical density were calculated. According to the salvage treatment after local recurrence, all cases were divided into the salvage surgery group, second-course chemoradiotherapy group and immunochemotherapy group. The differences of survival outcomes and incidence rates of esophageal tracheal fistula, hemorrhage, pericardial effusion, radiation pneumonitis, radiation esophagitis were analyzed among the three groups. The differences of survival rates were analyzed by Kaplan-Meier method and compared by log-rank test among groups.Results:The expression of collagen fibers in recurrent esophageal squamous cell carcinoma was significantly higher than that in primary esophageal squamous cell carcinoma. Collagen fiber expression was gradually down-regulated with the prolongation of recurrence time. The expression of collagen fibers in recurrent cases after 7 years was similar to that of primary esophageal squamous cell carcinoma. The 1-, 2- and 3-year survival rates of patients in the salvage surgery group, the second-course chemoradiotherapy group and the immunochemotherapy group were 47%, 30%, 20%; 50%, 27%, 15% and 72.5%, 50%, 50%, respectively; Immunochemotherapy was more effective in salvage treatment for recurrent esophageal squamous cell carcinoma, but there was no statistical difference.Conclusions:Collagen fibers are abundant in recurrent esophageal squamous cell carcinoma after radical chemoradiotherapy. With prolongation of recurrent interval, the expression of collagen fibers is down-regulated. The survival outcomes of patients in the immunochemotherapy group, salvage surgery group and second-course chemoradiotherapy group were comparable.

Objective:To investigate the activation of ubiquitin proteasome system (UPS) and autophagy in brain tissues of rats after severe traumatic brain injury (sTBI) and the role of autophagy in secondary traumatic brain injury.Methods:(1) Twenty-five SD rats were randomly divided into sham-operated group, group of 3 h after sTBI, group of 1 d after sTBI, group of 3 d after sTBI and group of 7 d after sTBI ( n=5). Only bone window was opened in sham-operated group, and controlled cortical impact (CCI)-induced sTBI models were established in the other 4 groups. Western blotting was used to detect the expressions of free ubiquitin, ubiquitinated protein, vacuolar protein sorting 34 (VPS34), P62, microtubule-associated protein-light chain 3-II, and Mature-cathepsin D (CTSD). (2) One hundred SD rats were randomly divided into normal control group, sTBI group, lactacystin group and SAR405 group ( n=25). Ten μL lactacystin or SAR405 were stereotactically injected into the lateral ventricle of lactacystin group and SAR405 group, respectively; 30 min after that, CCI-induced sTBI models were established in the sTBI group, lactacystin group and SAR405 group. Three d after modeling, the expressions of ubiquitinated protein, LC3-II, P62, and Caspase-3 were detected by Western blotting; percentage of brain water content was determined by dry/wet weight ratio; neurological functions were assessed by modified neurological deficit scale (mNSS); degrees of brain tissue damage were detected by HE staining; and cerebral blood perfusion was detected by laser scattering hemodynamic imaging system. Results:(1) Compared with sham-operated group, group of 3 h after sTBI, group of 1 d after sTBI, group of 3 d after sTBI and group of 7 d after sTBI had significantly decreased free ubiquitin, and group of 1 d after sTBI, group of 3 d after sTBI and group of 7 d after sTBI had significantly increased ubiquitinated protein in the brain tissues surrounding the injury lesions ( P<0.05). Compared with sham-operated group, group of 3 d after sTBI and group of 7 d after sTBI had statistically increased VPS34 and Mature-CTSD and significantly decreased P62 and group of 1 d after sTBI, group of 3 d after sTBI and group of 7 d after sTBI had significantly increased LC3-II in the brain tissues surrounding the injury lesions ( P<0.05). (2) The ubiquitinated protein relative expressions in the brain tissues surrounding the injury lesions of normal control group, sTBI group, lactacystin group and SAR405 group were 4.78±2.63, 10.62±0.73, 13.45±1.22 and 8.50±0.83, respectively, with significant differences ( P<0.05). Compared with the normal control group, the sTBI group, lactacystin group and SAR405 group had significantly higher LC3-II, ubiquitinated protein and cleaved caspase-3/pro-caspase-3, and significantly lower P62 in the brain tissues surrounding the injury lesions ( P<0.05); compared with the the sTBI group, the lactacystin group had significantly higher LC3-II, ubiquitinated protein, and cleaved caspase-3/pro-caspase-3, and significantly lower P62 in the brain tissues surrounding the injury lesions ( P<0.05); compared with the the sTBI group, the SAR405 group had significantly lower LC3-II, ubiquitinated protein and cleaved caspase-3/pro-caspase-3, and significantly higher P62 in the brain tissues surrounding the injury lesions ( P<0.05). Compared with the normal control group([67.60±2.51]%、[0±0] scores、[333.41±46.86] PU), the sTBI group, lactacystin group and SAR405 group had statistically higher percentage of brain water content and mNSS scores ([80.2±1.30]%, [87.0±1.58]% and [71.60±1.81]%; 13.8±1.10, 16.4±0.55 and 10.40±1.14) and signficantly lower cerebral blood perfusion volume ([53.98±5.99] PU, [21.71±2.62] PU and [87.97±6.75] PU, P<0.05); compared with the sTBI group, the lactacystin group had significantly higher brain water content and mNSS scores, and significantly lower cerebral blood perfusion volume ( P<0.05); compared with the sTBI group, the SAR405 group had significantly lower brain water content and mNSS scores, and significantly higher cerebral blood perfusion volume ( P<0.05). HE staining showed that the cortical tissues were most severely damaged in the lactacystin group, followed by the sTBI group; the least damage was noted in the SAR405 group, and no significant damage in the normal control group was noted. Conclusion:After sTBI, UPS activation is earlier than autophagy; autophagy inhibition helps to alleviate UPS dysfunction, reduce Caspase-3-induced apoptosis, and is beneficial to the recovery of neurological function.

Objective:To explore the spatial support capacity and its influence in osteogenic effect of composite biofilm based on poly(propylene carbonate)(PPC)/poly(butylene succinate)(PBS)in rabbit tibial bone defect models,and to clarify its barrier functional reliability and osteogenetic effect in vivo.Methods:The composite biofilms of PPC/PBS and PPC/PBS/collegen type Ⅰ(Col-Ⅰ)(PPC/PBS/Co)were prepared.Eighteen Japanese big-ear rabbits were selected and two bone defects were prepared on each side of the tibia of the rabbits.Six rabbits were randomly selected to place PPC/PBS composite biofilm on the bone defects,2 rabbits were executed at 2,4,8 and 12 weeks after operation,and the surface microstructures of PPC/PBS composite biofilm in the rabhit bone defect area were observed by scanning electron microscope(SEM).The experiment was divided into blank control group,PPC/PBS composite biofilm group,BME-10X collagen membrane group,and PPC/PBS/Co composite biofilm group.The above biofilms were placed on the corresponding bone defects of rabbits by operation,while no biofilm was placed in the rabbits in blank control group.Three rabbits were killed at 2,4,8 and 12 weeks after operation respectively,and the gray values of regenerated bone in the bone defect areas of the rabbits in varrous groups were detected by soft X-ray;the fluorescence intensities of regenerated bone tissue in the bone defect areas of the rabbits in various groups were observed by laser scanning confocal microscope after fluorescence labeling.The pathomorphology of regenerated bone tissue in the bone defect areas of the rabbits in various groups were observed by HE staining and modified Gomori staining,and the expression levels of bone morphogenetic protein 2(BMP-2)and osteopontin(OPN)in the regenerated bone tissue in bone defect areas of the rabbits in various groups were detected by immunohistochemical staining.Results:In general,the PPC/PBS composite biofilm was tightly covered in the bone defect area without displacement and collapse.The SEM results showed that the porous surface of PPC/PBS composite biofilm appeared micropore structure and the number of micropores was increased with the prolongation of time,while the smooth surface of biofilm basically did not form the micropore-like structure.The results of soft X-ray detection showed that the gray values of regenerated bone tissue in bone defect areas of the rabbits in various groups were increased with the prolongation of time,and the gray value of regenerated bone tissue in bone defect areas of the rabbits in PPC/PBS/Co composite biofilm group was significantly higher than those in other groups(P＜0.05).The confocal micrscope results showed that the fluorescence intensity of regenerated bone tissue in bone defect areas of the rabbits in PPC/PBS/Co composite biofilm group was similar to those in blank control group at 4,8,and 12 weeks;compared with PPC/PBS composite biofilm group and BME-10X collagen membrane group,the fluoresence intensity of regenerated bone tissue in bone defect areas of the rabbits in PPC/PB/Co composite biofilm group at 4 weeks was increased(P＜0.05),and the fluoresence intensity of regenerated bone tissue in bone defect areas of the rabbits at 8 and 12 weeks were decreased(P＜0.05).The results of HE staining and modified Gomori staining showed that compared with PPC/PBS composite biofilm group and BME-10X collagen membrane group,the new bone formed faster in PPC/PBS/Co composite biofilm group and blank control group at 2 and 4 weeks,and the lamellar bone mineralization was higher at 12 weeks.The immunohistochemical staining results showed that compared with blank control group,PPC/PBS composite biofilm group and BME-10X collagen membrane group,the expression levels of BMP-2 and OPN proteins in the regenerated bone tissue in bone defect areas of the rabbits in PPC/PBS/Co composite biofilm group at 2 and 4 weeks were increased(P＜0.05 or P＜0.01);compared with blank control group and PPC/PBS composite biofilm group,the expression levels of BMP-2 and OPN proteins in the regenerated bone tissue in bone defect areas of the rabbits in BME-10X collage membrane group were decreased(P＜0.05 or P＜0.01).Conclusion:PPC/PBS composite biofilm has excellent spatial support capacity and reliable physical barrier function.The PPC/PBS/Co composite biofilm has a good effect in guiding bone regeneration in vivo.

Objective:To screen the factors influencing overall survival (OS) of patients undergoing radical resection for colorectal cancer (CRC) and to construct a prognostic model for OS of patients after CRC.Methods:The clinical data of 350 patients with stage Ⅰ-Ⅳ CRC who underwent radical resection in the People's Hospital of Wuhan University from March 2017 to December 2019 were collected retrospectively. Patients were divided into subgroups 0 ( n=70), 1 ( n=172), and 2 ( n=108) according to different preoperative systemic inflammation score (SIS). The relationship between different SIS, neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), systemic immune inflammation index (SII) and prognosis of CRC patients undergoing radical surgical resection were analyzed, and Cox regression models were used to perform univariate and multifactorial analyses of factors affecting patient prognosis, and column line graph models were constructed based on the results of multifactorial analyses. Results:By the deadline of follow-up, 80 of 350 CRC patients died, and the 5-year OS rate was 77.14%. The 5-year survival rates of patients in SIS group 0, group 1 and group 2 were 95.71%, 79.65% and 61.11% respectively, with a statistically significant difference ( χ2=30.19, P<0.001). Statistically significant differences in age ( χ2=19.40, P<0.001), tumor site ( χ2=8.18, P=0.017), T stage ( χ2=10.01, P=0.007), TNM stage ( χ2=14.80, P=0.001), tumor diameter ( χ2=13.91, P=0.001) and carcino-embryonic antigen (CEA) level ( χ2=10.12, P=0.006) among patients in SIS group 0, group 1 and group 2. The 5-year OS rates of patients in the low NLR and high NLR groups were 82.67% and 56.16% respectively, with a statistically significant difference ( χ2=24.96, P<0.001) ; the 5-year OS rates of patients in the low LMR and high LMR groups were 66.85% and 88.17% respectively, with a statistically significant difference ( χ2=22.45, P<0.001) ; the 5-year OS rates of patients in the low SII and high SII groups were 86.14% and 69.02% respectively, with a statistically significant difference ( χ2=14.76, P<0.001). Univariate analysis showed that age ( HR=2.58, 95% CI: 1.54-4.32, P<0.001), T stage ( HR=2.41, 95% CI: 1.24-4.68, P=0.009), N stage ( HR=3.03, 95% CI: 1.85-4.94, P<0.001), TNM stage ( HR=3.61, 95% CI: 2.15-6.04, P<0.001), nerve invasion ( HR=1.97, 95% CI: 1.27-3.08, P=0.002), vascular invasion ( HR=2.31, 95% CI: 1.49-3.59, P<0.001), preoperative SIS 1 score ( HR=5.09, 95% CI: 1.57-16.56, P=0.007), SIS 2 score ( HR=11.05, 95% CI: 3.42-35.65, P<0.001), NLR ( HR=2.97, 95% CI: 1.90-4.64, P<0.001), LMR ( HR=0.31, 95% CI: 0.19-0.52, P<0.001), and SII ( HR=2.50, 95% CI: 1.54-4.06, P<0.001) were all independent influence factors affecting the postoperative prognosis of CRC patients undergoing radical surgical resection; multivariate analysis showed that age >60 years ( HR=2.27, 95% CI: 1.31-3.91, P=0.003), TNM stage Ⅲ-Ⅳ ( HR=7.08, 95% CI: 1.89-26.59, P=0.004), and preoperative SIS 2 score ( HR=4.02, 95% CI: 1.09-14.83, P=0.037) were all independent risk factors affecting the postoperative prognosis of CRC patients undergoing radical surgical resection. The nomogram model built based on the screened variables has high prediction accuracy: the C-index of the nomogram was 0.75. Conclusion:Age>60 years old, TNM stage Ⅲ-Ⅳ, SIS 2 score are all independent risk factors for postoperative prognosis of colorectal cancer. The nomograph model constructed by this method has high prediction accuracy.

ObjectiveTo establish an animal model of autologous arteriovenous fistula in mice and evaluate its effect. MethodsThe left external jugular vein and common carotid artery of 10 8-week-old male C57BL/6 mice were separated by end-to-side anastomosis of external jugular vein and common carotid artery after anesthesia, and the right jugular vein was exposed without suture as a control, so as to establish an animal model of internal arteriovenous fistula. Doppler ultrasound, HE and Masson staining and immunohistochemical staining were used to observe the hemodynamics, intimal hyperplasia and protein expression of smooth muscle cell proliferation in the outflow vein of the internal arteriovenous fistula and the contralateral control vein, and to evaluate the effect of model construction. ResultsA total of 10 mice were selected for this study, and 9 mice were successfully modeled, with a success rate of 90%. Ultrasound examinations were performed on the day of surgery, 7 and 14 days after surgery, respectively. The results showed that the flow velocity near the anastomosis was linearly correlated with the diameter of the tube. The higher the flow velocity, the larger the diameter of the tube. There was a positive correlation between peak velocity and lumen diameter (P=0.000 6, R²=0.831 7). After surgery 14 days, HE staining results showed that after autologous arteriovenous fistula molding, the average lumen area of outflow segment vein was significantly decreased (P < 0.000 1), the intima area was significantly increased (P < 0.000 1), the intimal area was significantly increased (P < 0.000 1). On the surgical side of arteriovenous fistula, collagen deposition was significantly increased, and the proportion of Masson-positive regions was significantly increased (P < 0.000 1). Immunohistochemical staining showed that the proportion of collagen 1 positive areas on the surgical side of arteriovenous fistula was significantly upregulated (P < 0.000 1), and α-smooth muscle actin (α-SMA) , proliferating cell nuclear antigen (PCNA) positive cells increased significantly (P < 0.000 1), indicating an increase in local cell proliferation level. ConclusionThe established mouse autologous arteriovenous fistula model has the advantages of high success rate, good stability and low cost. The model provides a good carrier for exploring the biological mechanism of intimal hyperplasia in arteriovenous fistulas.