BACKGROUND: Oral squamous cell carcinoma (OSCC) is a prevalent type of cancer with a high mortality rate in its late stages. One of the major challenges in OSCC treatment is the resistance to epidermal growth factor receptor (EGFR) inhibitors. Therefore, it is imperative to elucidate the mechanism underlying drug resistance and develop appropriate precision therapy strategies to enhance clinical efficacy. METHODS: To evaluate the efficacy of the combination of the Ca 2+ /calmodulin-dependent protein kinase II (CAMK2) inhibitor KN93 and EGFR inhibitors, we performed in vitro and in vivo experiments using two FAT atypical cadherin 1 ( FAT1 )-deficient (SCC9 and SCC25) and two FAT1 wild-type (SCC47 and HN12) OSCC cell lines. We assessed the effects of EGFR inhibitors (afatinib or cetuximab), KN93, or their combination on the malignant phenotype of OSCC in vivo and in vitro . The alterations in protein expression levels of members of the EGFR signaling pathway and SRY-box transcription factor 2 (SOX2) were analyzed. Changes in the yes-associated protein 1 (YAP1) protein were characterized. Moreover, we analyzed mitochondrial dysfunction. Besides, the effects of combination therapy on mitochondrial dynamics were also evaluated. RESULTS: OSCC with FAT1 mutations exhibited resistance to EGFR inhibitors treatment. The combination of KN93 and EGFR inhibitors significantly inhibited the proliferation, survival, and migration of FAT1 -mutated OSCC cells and suppressed tumor growth in vivo . Mechanistically, combination therapy enhanced the therapeutic sensitivity of FAT1 -mutated OSCC cells to EGFR inhibitors by modulating the EGFR pathway and downregulated tumor stemness-related proteins. Furthermore, combination therapy induced reactive oxygen species (ROS)-mediated mitochondrial dysfunction and disrupted mitochondrial dynamics, ultimately resulting in tumor suppression. CONCLUSION Combination therapy with EGFR inhibitors and KN93 could be a novel precision therapeutic strategy and a potential clinical solution for EGFR-resistant OSCC patients with FAT1 mutations.
Humans ; ErbB Receptors/metabolism* ; Mouth Neoplasms/metabolism* ; Cell Line, Tumor ; Animals ; Drug Resistance, Neoplasm/genetics* ; Cadherins/metabolism* ; Carcinoma, Squamous Cell/metabolism* ; Mice ; Mutation/genetics* ; Mice, Nude ; Protein Kinase Inhibitors/therapeutic use* ; Cetuximab/pharmacology* ; Afatinib/therapeutic use* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects*

Objective We aimed to evaluate the efficacy and safety of Shengxuebao Mixture in the treatment of cancer-related anemia(CRA)presenting with syndrome of deficiency of liver and kidney combined with syndrome of deficiency of both qi and blood.Methods A randomized,double-blind,placebo-controlled,multicenter clinical trial was conducted.Eligible patients with malignant tumors meeting the inclusion and exclusion criteria were enrolled from 26 hospitals,including Dongzhimen Hospital,Beijing University of Chinese Medicine,Xiaogan Central Hospital,and Yangzhou Hospital of Traditional Chinese Medicine,from June 1,2022,to September 30,2024.Patients were allocated 1:1 to either the experimental group receiving Shengxuebao Mixture or the control group receiving its simulator(placebo)using a block randomization method under double-blind conditions.Both groups received 15 mL orally three times daily for 28 consecutive days.The primary efficacy indicators included the hemoglobin(Hb)improvement rate(RHb)and the traditional Chinese medicine(TCM)syndrome improvement rate(RTCM)at week 4 of treatment.The secondary efficacy indicators encompassed Hb and red blood cell(RBC)count,Karnofsky Performance Status(KPS)score,TCM syndrome score,individual TCM symptom scores,and changes in each of these indicators compared to the baseline period at weeks 2,4,and 6 of treatment.Safety evaluations were conducted at week 4 of treatment.Results A total of 239 patients were enrolled,with 225 cases included in the Full Analysis Set(FAS)(109 in the experimental group vs.116 control group),163 in the Per Protocol Set(PPS)(77 vs.86),and 225 in the Safety Set(SS)(109 vs.116).Baseline characteristics between groups showed no significant differences.Significant differences were observed between the experimental and control groups in RHb at week 4(FAS:49.51%vs.35.24%,P<0.05;PPS:53.25%vs.36.05%,P<0.05)and RTCM at week 4(FAS:61.54%vs.39.62%,P<0.01;PPS:64.94%vs.40.70%,P<0.01).At weeks 2,4,and 6,the experimental group showed greater improvements in Hb and RBC counts than the control group.Additionally,the TCM syndrome scores were lower in the experimental group than in the control group at these time points.Except for week 2 in PPS,the KPS improvement was better in the experimental group than in the control group(P<0.05).The experimental group also demonstrated a greater reduction in scores for individual TCM symptoms such as spiritlessness and weakness,poor appetite and reduced food intake at weeks 4 and 6 compared to the control group(P<0.05,P<0.01).Furthermore,the reduction in vertigo score was more pronounced in the experimental group at week 6(P<0.01).For the score of pale and lusterless complexion,only in the PPS was the reduction from baseline more significant in the experimental group than in the control group at weeks 4 and 6(P<0.05).No significant differences were observed between the experimental and control groups in the incidence of all adverse events or drug-related adverse reactions.Conclusion Shengxuebao Mixture demonstrates significant efficacy in patients with CRA presenting syndrome of deficiency of liver and kidney combined with syndrome of deficiency of both qi and blood,effectively increasing Hb levels,ameliorating TCM syndromes,alleviating clinical symptoms,and enhancing functional status,with no significant difference in adverse drug reactions compared to the placebo.

Objective We aimed to evaluate the efficacy and safety of Shengxuebao Mixture in the treatment of cancer-related anemia(CRA)presenting with syndrome of deficiency of liver and kidney combined with syndrome of deficiency of both qi and blood.Methods A randomized,double-blind,placebo-controlled,multicenter clinical trial was conducted.Eligible patients with malignant tumors meeting the inclusion and exclusion criteria were enrolled from 26 hospitals,including Dongzhimen Hospital,Beijing University of Chinese Medicine,Xiaogan Central Hospital,and Yangzhou Hospital of Traditional Chinese Medicine,from June 1,2022,to September 30,2024.Patients were allocated 1:1 to either the experimental group receiving Shengxuebao Mixture or the control group receiving its simulator(placebo)using a block randomization method under double-blind conditions.Both groups received 15 mL orally three times daily for 28 consecutive days.The primary efficacy indicators included the hemoglobin(Hb)improvement rate(RHb)and the traditional Chinese medicine(TCM)syndrome improvement rate(RTCM)at week 4 of treatment.The secondary efficacy indicators encompassed Hb and red blood cell(RBC)count,Karnofsky Performance Status(KPS)score,TCM syndrome score,individual TCM symptom scores,and changes in each of these indicators compared to the baseline period at weeks 2,4,and 6 of treatment.Safety evaluations were conducted at week 4 of treatment.Results A total of 239 patients were enrolled,with 225 cases included in the Full Analysis Set(FAS)(109 in the experimental group vs.116 control group),163 in the Per Protocol Set(PPS)(77 vs.86),and 225 in the Safety Set(SS)(109 vs.116).Baseline characteristics between groups showed no significant differences.Significant differences were observed between the experimental and control groups in RHb at week 4(FAS:49.51%vs.35.24%,P<0.05;PPS:53.25%vs.36.05%,P<0.05)and RTCM at week 4(FAS:61.54%vs.39.62%,P<0.01;PPS:64.94%vs.40.70%,P<0.01).At weeks 2,4,and 6,the experimental group showed greater improvements in Hb and RBC counts than the control group.Additionally,the TCM syndrome scores were lower in the experimental group than in the control group at these time points.Except for week 2 in PPS,the KPS improvement was better in the experimental group than in the control group(P<0.05).The experimental group also demonstrated a greater reduction in scores for individual TCM symptoms such as spiritlessness and weakness,poor appetite and reduced food intake at weeks 4 and 6 compared to the control group(P<0.05,P<0.01).Furthermore,the reduction in vertigo score was more pronounced in the experimental group at week 6(P<0.01).For the score of pale and lusterless complexion,only in the PPS was the reduction from baseline more significant in the experimental group than in the control group at weeks 4 and 6(P<0.05).No significant differences were observed between the experimental and control groups in the incidence of all adverse events or drug-related adverse reactions.Conclusion Shengxuebao Mixture demonstrates significant efficacy in patients with CRA presenting syndrome of deficiency of liver and kidney combined with syndrome of deficiency of both qi and blood,effectively increasing Hb levels,ameliorating TCM syndromes,alleviating clinical symptoms,and enhancing functional status,with no significant difference in adverse drug reactions compared to the placebo.

Objective To solve the problem of large data volume,multiple dimensions and low value for assisting traditional Chinese medicine clinical diagnosis in home health perception layer devices.Methods Based on the principles of traditional Chinese medicine diagnosis,this paper divides home health data into three types:complementary,redundant,and collaborative,and proposes a solution for data fusion at the levels of device data,home events,and traditional Chinese medicine symptoms.Results The proposed data fusion solution in this paper enables the data collected by various devices in the home environment to work together,extracts home data that is more valuable for traditional Chinese medicine diagnosis,and reduces the real-time pressure on the home network bandwidth caused by the sensors on the home side.Conclusion The construction of an open IoT ecosystem for home health based on multiple devices is a huge project,which includes the construction of perception layer hardware,data cleaning,fusion,normalization,labeling,modeling,and other aspects.This paper focuses on the idea of home health data fusion,which can provide directions for cleaning up heterogeneous data from multiple sources at home and also provide ideas for subsequent data labeling and modeling with traditional Chinese medicine characteristics,thus providing more valuable decision-making assistance for traditional Chinese medicine clinical practice.

Objective:To analyze the therapeutic effect of 3D printing technology combined with locking plate fixation on femoral shaft fracture in patients with femoral deformity.Methods:The clinical data of 33 patients with femoral shaft fracture with femoral deformity who met the inclusion criteria and underwent locking plate fixation in the Xi′an Honghui Hospital Affiliated to Xi′an Jiaotong University from June 2014 to December 2020 were retrospectively analyzed. The patients were divided into 3D printing group ( n=18) and control group ( n=15) according to whether 3D printing was performed before operation. The 3D printing group including 11 males and 7 females with an age of (46.78±13.76) years.The control group including 9 males and 6 females with an age of (48.20±14.27) years.The operation time, intraoperative blood loss, fracture healing time and complications of the two groups were recorded. Visual analogue scale (VAS) scores of pain were evaluated before and 6, 12, 24, 48 and 72 h after operation. According to the Harris hip score, the Hospital for Special Surgery (HSS) knee score and The MOS 36-item short-from Health Survey (SF-36), the hip and knee function and quality of life of the patients before and 12 months after injury were evaluated. The measurement data were represented as mean±standard deviation( ± s), and the comparison between groups was conducted using the t-test; the comparison of count data between groups was conducted by Chi-square test or Fisher exact probability. Results:The operation time, intraoperative blood loss, and incidence of complications in the 3D printing group were (91.50±9.07) min, (191.11±16.01) mL, and 0(0/18), respectively, and those in the control group were (118.07±14.19) min, (270.27±17.59) mL, and 26.7% (4/15), the differences between the two groups were statistically significant ( P <0.05). The pain VAS scores of the 3D printing group were significantly better than those of the control group at 6, 12, 24, 48, and 72 h after operation ( P<0.05). There were no differences in fracture healing time and preoperative pain VAS between the two groups( P>0.05). There were no significant differences in hip function, knee function and quality of life scores between the two groups before injury and 12 months after injury( P>0.05). Conclusion:In the treatment of femoral shaft fractures in patients with femoral deformity with locking plate fixation, the application of 3D printing technology can be used for preoperative design and plate preshaping, which can shorten the operation time, reduce the amount of intraoperative blood loss, reduce the VAS of pain and the incidence of complications, improve the satisfaction of surgery, and provide a new option for the treatment of femoral shaft fractures in patients with femoral deformity.

Objective:To explore the perioperative factors which influence the occurrence of prolonged postoperative ileus (PPOI) in patients with Crohn′s disease (CD) .Methods:A retrospective case-control study was conducted. Clinical data of CD patients who underwent partial intestinal resection at Jinling Hospital of Medical School of Nanjing University from June 2019 to January 2021 were analyzed retrospectively. The patients were divided into PPOI group and non-PPOI group according to whether the PPOI happened or not. The differences in perioperative indexes between PPOI and non-PPOI groups were assessed by univariate analysis. Spearman rank correlation test was used to exclude variables with strong correlations. The receiver operating characteristic (ROC) curve was performed to determine the cut-off values of the variables with P<0.05 in univariate analysis and clinical significance, and the variables were converted into binary qualitative data. And then the data were analyzed by multivariate Logistic regression to determine the independent risk factors of PPOI. Results:A total of 314 patients were included, including 202 males and 112 females with the age of (39 ± 14) years old. Eighty-nine (28.3%) patients with PPOI were set as PPOI group, and 225 (71.7%) patients without PPOI were set as non-PPOI group. Compared with non-PPOI group, patients in PPOI group had longer surgery duration [128 (99, 166) min vs. 110 (85, 141) min, P = 0.006], more total opioids [2.9 (2.4, 3.3) MME/kg vs. 2.7 (2.4, 3.1) MME/kg, P = 0.011, MME: morphine milligram equivalent], more intraoperative infusion volume ( P = 0.009), more crystal solution volume ( P = 0.007), higher intraoperative in-out balance per body weight (IOB/BW) [18.8 (14.1, 25.5) ml/kg vs. 16.4 (12.5, 20.7) ml/kg, P = 0.005], lower minimum level of albumin within 3 days after surgery ( P = 0.019), higher maximum change of albumin level after surgery ( P = 0.024), lower minimum concentration of serum potassium within 3 days after surgery ( P = 0.007), and more infusion supplement on the first day after surgery ( P<0.001), and longer postoperative hospital stay ( P<0.001). In the correlation analysis, there were strong correlations between intraoperative infusion volume and IOB/BW ( r = 0.689, P<0.001), and intraoperative infusion volume and crystal fluid volume ( r = 0.986, P<0.001) respectively. Therefore, intraoperative infusion volume and crystal fluid volume were excluded from the multivariate analysis. The cut-off value of the surgery duration was 123.5 min by ROC curve, the total opioids was 2.84 MME/kg, IOB/BW was 21.08 ml/kg, the minimum level of albumin and the minimum concentration of serum potassium within 3 days after surgery were 29.15 g/L and 3.75 mmol/L respectively, the maximum change of albumin level after surgery was 7.25 g/L, and the fluid supplement on the first day after surgery was 2751.5 ml. In multivariate Logistic regression analysis, surgery duration ≥ 123.5 min ( OR = 2.162, 95% CI: 1.260-3.710, P = 0.005), IOB/BW≥21.08 ml/kg ( OR = 3.184, 95% CI: 1.817-5.581, P<0.001), maximum change of albumin level ≥7.25 g/L after surgery ( OR = 1.948, 95% CI: 1.110-3.419, P = 0.02) and fluid supplement ≥2751.5 ml on the first day after surgery ( OR = 2.845, 95% CI: 1.630-4.966, P<0.001) were the independent risk factors for PPOI. Conclusions:CD patients who have the factors of long surgery duration, high IOB/BW, big change of albumin level after surgery and much fluid supplement on the first day after surgery are prone to PPOI. Therefore, controlling IOB/BW and fluid supplement on the first day after surgery are important measures to reduce the incidence of PPOI.

Objective:To explore the perioperative factors which influence the occurrence of prolonged postoperative ileus (PPOI) in patients with Crohn′s disease (CD) .Methods:A retrospective case-control study was conducted. Clinical data of CD patients who underwent partial intestinal resection at Jinling Hospital of Medical School of Nanjing University from June 2019 to January 2021 were analyzed retrospectively. The patients were divided into PPOI group and non-PPOI group according to whether the PPOI happened or not. The differences in perioperative indexes between PPOI and non-PPOI groups were assessed by univariate analysis. Spearman rank correlation test was used to exclude variables with strong correlations. The receiver operating characteristic (ROC) curve was performed to determine the cut-off values of the variables with P<0.05 in univariate analysis and clinical significance, and the variables were converted into binary qualitative data. And then the data were analyzed by multivariate Logistic regression to determine the independent risk factors of PPOI. Results:A total of 314 patients were included, including 202 males and 112 females with the age of (39 ± 14) years old. Eighty-nine (28.3%) patients with PPOI were set as PPOI group, and 225 (71.7%) patients without PPOI were set as non-PPOI group. Compared with non-PPOI group, patients in PPOI group had longer surgery duration [128 (99, 166) min vs. 110 (85, 141) min, P = 0.006], more total opioids [2.9 (2.4, 3.3) MME/kg vs. 2.7 (2.4, 3.1) MME/kg, P = 0.011, MME: morphine milligram equivalent], more intraoperative infusion volume ( P = 0.009), more crystal solution volume ( P = 0.007), higher intraoperative in-out balance per body weight (IOB/BW) [18.8 (14.1, 25.5) ml/kg vs. 16.4 (12.5, 20.7) ml/kg, P = 0.005], lower minimum level of albumin within 3 days after surgery ( P = 0.019), higher maximum change of albumin level after surgery ( P = 0.024), lower minimum concentration of serum potassium within 3 days after surgery ( P = 0.007), and more infusion supplement on the first day after surgery ( P<0.001), and longer postoperative hospital stay ( P<0.001). In the correlation analysis, there were strong correlations between intraoperative infusion volume and IOB/BW ( r = 0.689, P<0.001), and intraoperative infusion volume and crystal fluid volume ( r = 0.986, P<0.001) respectively. Therefore, intraoperative infusion volume and crystal fluid volume were excluded from the multivariate analysis. The cut-off value of the surgery duration was 123.5 min by ROC curve, the total opioids was 2.84 MME/kg, IOB/BW was 21.08 ml/kg, the minimum level of albumin and the minimum concentration of serum potassium within 3 days after surgery were 29.15 g/L and 3.75 mmol/L respectively, the maximum change of albumin level after surgery was 7.25 g/L, and the fluid supplement on the first day after surgery was 2751.5 ml. In multivariate Logistic regression analysis, surgery duration ≥ 123.5 min ( OR = 2.162, 95% CI: 1.260-3.710, P = 0.005), IOB/BW≥21.08 ml/kg ( OR = 3.184, 95% CI: 1.817-5.581, P<0.001), maximum change of albumin level ≥7.25 g/L after surgery ( OR = 1.948, 95% CI: 1.110-3.419, P = 0.02) and fluid supplement ≥2751.5 ml on the first day after surgery ( OR = 2.845, 95% CI: 1.630-4.966, P<0.001) were the independent risk factors for PPOI. Conclusions:CD patients who have the factors of long surgery duration, high IOB/BW, big change of albumin level after surgery and much fluid supplement on the first day after surgery are prone to PPOI. Therefore, controlling IOB/BW and fluid supplement on the first day after surgery are important measures to reduce the incidence of PPOI.

Objective:To investigate changes in serum C3d and C5b-9 levels in elderly patients with idiopathic membranous nephropathy(IMN)and their correlations with prognosis.Methods:Two hundred thirty-one elderly patients with IMN and 96 non-elderly patients with IMN confirmed by kidney biopsy at the First Affiliated Hospital of Zhengzhou University from January 2015 to May 2017 were enrolled.During the same period, 118 healthy individuals receiving health checkups were included as controls.Patients were divided into the low C3d group( n=112)and the high C3d group( n=113)according to the median level of serum C3d.Serum C3d and C5b-9 levels were measured by enzyme-linked immunosorbent assays. Results:Serum C3d and C5b-9 levels in elderly IMN patients were 0.23(0.15, 0.45)mg/L and 0.28(0.20, 1.23)mg/L, respectively, which were higher than those in healthy controls[0.18(0.13, 0.22)mg/L, 0.22(0.16, 0.26)mg/L, respectively]( Z=-4.261 and -6.213, P<0.001). Serum C3d levels in elderly and non-elderly IMN patients were correlated negatively with the estimated glomerular filtration rate( r=-0.155 and -0.426, P=0.019 and 0.000), but positively with serum creatinine, anti-phospholipase A2 receptor(PLA2R)antibody levels and 24 h urinary protein( r=0.184, 0.326, 0.407, 0.321 and 0.145, P=0.005, 0.001, 0.000, 0.001 and 0.027). Kaplan-Meier survival analysis showed that the cumulative renal survival rate in elderly IMN patients was lower in the high C3d group than in the low C3d group(47.8% vs.70.8%, Log Rank χ2=7.399, P=0.007). Multivariate Cox regression analysis showed that high C3d levels were an independent risk factor for poor renal outcomes in elderly IMN patients( HR=2.288, 95% CI: 1.082-4.839, P=0.030). Conclusions:High serum C3d levels are associated with increases in urinary protein excretion and anti-PLA2R antibody levels, renal function decline, and poor renal outcomes in elderly IMN patients.

Objective:To detect serum level of complement factor B (CFB), and to explore its correlations with clinical parameters and prognosis in children with primary IgA nephropathy (IgAN).Methods:A total of 204 children with primary IgAN confirmed by kidney biopsy in the Department of Nephrology of the First Affiliated Hospital of Zhengzhou University from December 2014 to April 2017 were included in IgAN group.During the same period, 84 healthy children were included in healthy control group.Their mean age was (11.0±3.5) years and (10.9±3.2) years, respectively.Patients in IgAN group were divided into low CFB group (102 cases) and high CFB group (102 cases) according to the medium serum level of CFB measured by enzyme-linked immunosorbent assay. Spearman′ s coefficient was employed to analyze correlation amongst various parameters.Multivariable-adjusted Cox proportional ha-zards models were used to evaluate the relationship between serum CFB level and prognosis in children with IgAN. Results:Serum CFB levels were significantly higher in IgAN group than that in healthy control group [290.9 (186.2-453.9) mg/L vs.218.9 (155.0-321.3) mg/L, Z=-3.372, P=0.001]. Serum levels of CFB were negatively correlated with serum albumin ( r=-0.388, P<0.001) and estimated glomerular filtration rate ( r=-0.416, P<0.001), but positively correlated with serum creatinine ( r=0.305, P<0.001) and 24 h urinary protein ( r=0.456, P<0.001) in IgAN group.The incidences of crescents (C1-2) (70.6% vs.29.4%, χ2=34.588, P<0.001) and C 3 deposition (+ + -+ + + ) (63.7% vs.44.1%, χ2=7.892, P=0.005) were significantly higher in high CFB group than those in low CFB group. Kaplan- Meier analysis showed that high CFB levels predicted worse renal outcome in pediatric IgAN patients ( χ2=17.509, P<0.001). Multivariate Cox regression analysis showed that the high CFB level was the independent risk factor for the poor renal outcome ( HR=2.517, 95% CI: 1.284-4.932, P=0.007). Conclusions:High serum levels of CFB are associated with decreased renal function, increased urinary protein excretion, crescentic formation and poor renal outcome in pediatric IgAN patients.

Accurately understanding the features and connotations of complex engineering problems is an important prerequisite for setting graduation requirements, constructing curriculum and designing teaching contents. By discussing the characteristics of complex engineering problems in the biological industry, this paper explored the demands for undergraduates in Yangtze river delta region, summarized the typical jobs and their requirements, and expounded the connotation of complex engineering problems contained in various typical tasks. On this basis, a gradual curriculum system was constructed, which included multiple stages of conceiving, formation and application, to cultivate the ability to solve complex engineering problems in the major of bioengineering. The curriculum coordinated the implementation of deep integration of industry and education, research feed back course construction, course team and advanced courses building up, professional associations covered all crews and students, supporting the ability training of solving complex engineering problems.
Biotechnology ; Curriculum ; Engineering ; Humans ; Industry ; Problem Solving