BACKGROUND: In China, lung cancer remains the cancer with the highest incidence and mortality rate. Among early-stage lung adenocarcinomas (LUAD), the micropapillary (MPP) component is prevalent and typically exhibits high aggressiveness, significantly correlating with early metastasis, lymphatic infiltration, and reduced five-year survival rates. Therefore, the study is to explore the similarities and differences between MPP and non-micropapillary (non-MPP) components in malignant pulmonary nodules characterized by GGOs in early-stage LUAD, identify unique mutational features of the MPP component and analyze the relationship between the ZNF469 gene, a member of the zinc-finger protein family, and the prognosis of early-stage LUAD, as well as its correlation with immune infiltration. METHODS: A total of 31 malignant pulmonary nodules of LUAD were collected and dissected into paired MPP and non-MPP components using microdissection. Whole-exome sequencing (WES) was performed on the components of early-stage malignant pulmonary nodules. Mutational signatures analysis was conducted using R packages such as maftools, Nonnegative Matrix Factorization (NMF), and Sigminer to unveil the genomic mutational characteristics unique to MPP components in invasive LUAD compared to other tumor tissues. Furthermore, we explored the expression of the ZNF469 gene in LUAD using The Cancer Genome Atlas (TCGA) database to investigate its potential association with the prognosis. We also investigated gene interaction networks and signaling pathways related to ZNF469 in LUAD using the GeneMANIA database and conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Lastly, we analyzed the correlation between ZNF469 gene expression and levels of immune cell infiltration in LUAD using the TIMER and TISIDB databases. RESULTS: MPP components exhibited a higher number of genomic variations, particularly the 13th COSMIC (Catalogue of Somatic Mutations in Cancer) mutational signature characterized by the activity of the cytidine deaminase APOBEC family, which was unique to MPP components compared to non-MPP components in tumor tissues. This suggests the potential involvement of APOBEC in the progression of MPP components in early-stage LUAD. Additionally, MPP samples with high similarity to APOBEC signature displayed a higher tumor mutational burden (TMB), indicating that these patients may be more likely to benefit from immunotherapy. The expression of ZNF469 was significantly upregulated in LUAD compared to normal tissue, and was associated with poor prognosis in LUAD patients (P<0.05). Gene interaction network analysis and GO/KEGG enrichment analysis revealed that COL6A1, COL1A1, COL1A2, TGFB2, MMP2, COL8A2 and C2CD4C interacted with ZNF469 and were mainly involved in encoding collagen proteins and participating in the constitution of extracellular matrix. ZNF469 expression was positively correlated with immune cell infiltration in LUAD (P<0.05). CONCLUSIONS The study has unveiled distinctive mutational signatures in the MPP components of early-stage invasive LUAD in the Asian population. Furthermore, we have identified that the elevated expression of mutated ZNF469 impacts the prognosis and immune infiltration in LUAD, suggesting its potential as a diagnostic and prognostic biomarker in LUAD.
Humans ; Lung Neoplasms/genetics* ; Adenocarcinoma of Lung/genetics* ; China ; Prognosis ; Transcription Factors

OBJECTIVE To evaluate the palatability and chewability of chewable tablets， and provide reference for the quality evaluation of various types of chewable tablets. METHODS Using self-made Glucosamine hydrochloride chewable tablets as the model drug， the quality test was conducted. The in vitro simulation system for chewable tablets was established by using a texture analyzer and rheometer， and an oral simulation experiment was conducted on chewable tablets. The texture analyzer was used to measure the force required for chewing and simulate the static disintegration process of chewable tablets； the rheometer was adopted to measure the viscoelasticity， thixotropy， and deformability of chewable tablets during the chewing process. RESULTS The disintegration time limit， principal component content， and dissolution of self-made Glucosamine hydrochloride chewable tablets all met the limit requirements. The in vitro simulation results of the texture analyzer showed that self-made chewable tablets were easy to chew in both axial and radial directions， and the force required for chewing was within the range of the chewing force of the teeth； chewable tablets could disintegrate at an appropriate time without being chewed and only taken in the oral cavity. The in vitro simulation results of the rheometer showed that the chewable tablets in the oral cavity exhibited a behavior of elasticity as the main factor and viscosity as the secondary factor through the continuous stirring of the tongue， and the viscosity of the chewable tablets gradually decreased with tongue stirring or tooth chewing； when chewing with teeth， the internal force of the chewing tablets decreased， causing plastic deformation and crushing. After being crushed， the shape couldn’t be restored， making it easy to chew and swallow. CONCLUSIONS The combination of texture analyzer and rheometer can be used to simulate the oral chewing process and evaluate the palatability and chewability of self-made Glucosamine hydrochloride chewable tablets. This model can provide reference for the evaluation of various chewable tablets.

OBJECTIVE To investigate the effects and mechanism of Yiqi huoxue decoction （YQHX） on lumbar disc herniation in rats. METHODS Rats were randomly divided into sham operation group， model group， NF-κB inhibitor group （QNZ group， 1 mg/kg）， YQHX group （9.1 g/kg） and combination group （YQHX+QNZ group， the same dose as each single drug group）， with 10 rats in each group. Except for sham operation group， lumbar disc herniation model of rats was induced in other groups； administration groups were given QNZ intraperitoneally or/and YQHX intragastrically， once a day， for 8 consecutive weeks. The severity of intervertebral disc herniation was evaluated in each group； the pathological changes of intervertebral discs and the changes of autophagy of nucleus pulposus cells were all observed； the level of tumor necrosis factor-α （TNF-α） in serum， and the ratios of Bcl-2/adenovirus E1B interacting protein 3 （BNIP3） and Beclin-1 positive cells in intervertebral disctissues were detected； the phosphorylation of nuclear factor-κB （NF-κB） p65， the expressions of tumor necrosis factor receptor- associated factor-2 （TRAF-2）， TRAF-3， BNIP3 and LC3B protein， and mRNA expressions of NF-κB p65， LC3B， p62，BNIP3 and Beclin-1 were determined. RESULTS Compared with model group， Pfirrmann grading score decreased significantly，the pathological injury of intervertebral disc tissue was relieved in YQHX group； the number of autophagosomes in nucleus pulposus cells increased； serum level of TNF-α and mRNA expression of p62 in intervertebral disc tissue decreased significantly； the ratios of BNIP3 and Beclin-1 positive cells， the phosphorylation of NF-κB p65， the expressions of TRAF-2， TRAF-3， BNIP3 and LC3B protein as well as the mRNA expressions of NF- κB p65， LC3B， BNIP3 and Beclin-1 decreased significantly in intervertebral disc tissues （P＜0.05）. The changes of above indexes in YQHX group were reversed partly in YQHX+QNZ group. CONCLUSIONS YQHX promotes the elevation of autophagy level of intervertebral discs， slows down the inflammatory response and the progression of lumbar disc herniation by activating the NF-κB signaling pathway.

Objective:To evaluate the efficacy of a calf tissue flap combined with antibiotic-loaded calcium sulfate (artificial bone or mixed iliac bone graft) in the treatment of foot and ankle osteomyelitis.Methods:A retrospective study was conducted to analyze the 11 cases of foot and ankle osteomyelitis which had been treated at Department of Hand and Microsurgery, The Third Hospital of Baoji from October 2018 to October 2021. There were 8 males and 3 females, aged (42.3±23.7) years. The chronic hypotoxic osteomyelitis was repaired and reconstructed after thorough debridement at one stage with a calf tissue flap combined with antibiotic-loaded calcium sulfate artificial bone to fill the cavity and cover the wound. The acute infected trauma was repaired and reconstructed after thorough debridement at the second stage with a calf tissue flap combined with antibiotic-loaded calcium sulfate artificial bone to fill the cavity and cover the wound only after the acute infection was controlled by local dressing, drainage or negative pressure therapy and systemic anti-infection treatment at the primary stage. The flap size ranged from 3.5 cm × 2.0 cm to 12.0 cm × 6.0 cm. Four cases were treated by a peroneal artery perforator flap combined with antibiotic-loaded calcium sulfate artificial bone, 3 cases by a flap with peroneal artery perforator and peroneal nerve trophic vessel combined with antibiotic-loaded calcium sulfate artificial bone, 3 cases by a posterior tibial artery perforator flap combined with antibiotic-loaded calcium sulfate artificial bone, and one by a peroneus longus muscle flap combined with antibiotic-loaded calcium sulfate artificial bone. Postoperatively, the flap survival, bone union time, ankle function and complications were observed; the therapeutic efficacy was evaluated by comparing infection control indexes at the final follow-up [clinical manifestations like local redness, swelling, pain, ulceration, and exudation, and white blood cell count (WBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and calcitoninogen (PCT)].Results:All the flaps survived except for one which developed necrosis at the distal 1/3 of the flap but responded to dressing change. All the patients were followed up for (22.6±11.5) months. The 6-month follow-up revealed that all the flaps were fine in shape and texture. Re-examinations showed that WBC, CRP, ESR and PCT were normal or close to normal, the local skin was free of redness, swelling or ulceration, and protective sensation was restored to varying degrees. X-ray at (12.1±2.3) months showed that lesions disappeared, bony union was achieved, the ankle joint regained basic flexion and extension, and the affected limb also regained weight-bearing and walking functions in all the patients but one whose X-ray at 18 months showed poor bony union but no other symptoms or signs.Conclusion:In the treatment of foot and ankle osteomyelitis, a calf tissue flap combined with antibiotic-loaded calcium sulfate artificial bone can promote bone healing and restore the function of the foot and ankle because it not only fills the cavity and covers the wound but also effectively controls the infection.

Objective:To evaluate the efficacy of total laparoscopic surgery vs. open surgery for hilar cholangiocarcinoma. Methods:The clinical data of 45 patients undergoing laparoscopic radical resection of hilar cholangiocarcinoma and 42 patients by open surgery from Mar 2017 to Mar 2021 were retrospectively analyzed.Results:There was no significant difference in demographics, Bismuth classification and excision extension between the two groups (all P>0.05). The laparoscopic surgery used longer time ( t=-1.366, P<0.05). The intraoperative blood loss, number of lymph node dissection and postoperative hospital stay favored laparoscopic method( t=0.043, t=0.026, t=-1.852, P<0.05). R 0 radical resection rate，postoperative complications were also in favor of laparoscopic surgery ( χ2=3.216, χ2=2.566, all P<0.05). There was no significant difference in postoperative pathology and in hospital expenses (all P>0.05). The 1- and 3-year survival rate of the laparoscopic group was superior (all P<0.05). Conclusions:In spite of longer operational time，patients in laparoscopic hilar cholangiocarcinoma radical resection group have shorter postoperative in hospital stay and longer postoperative survival time.

Objective:To observe the surgical method and clinical efficacy of applying calf tissue flap combined with artificial bone of antibiotics loaded calcium sulphate in treatment of tibia osteomyelitis.Methods:From July 2018 to January 2021, calf tissue flaps combined with artificial bone of antibiotics loaded calcium sulphate (or mixed with iliac bone) were applied to treat 16 cases with tibia osteomyelitis in the Department of Hand and Microsurgery of Baoji Third Hospital. There were 10 males and 6 females, aged 15 to 64 years old, with a mean age of 41 years old. For the 5 cases with acute osteomyelitis caused by wound infection, local dressing changes and drainage or VSD wound management were applied after debridement, together with primary systemic anti-infection treatment. After the acute infection period had been under control and stabilised, the wounds were then thoroughly exposed and cavities were filled and covered with the surgical reconstruction procedure with antibiotics-loaded artificial bone of calcium sulphate in combination with calf tissue flaps. For the 11 cases with chronic and hypotoxicity osteomyelitis, calf tissue flaps combined with antibiotics-blended artificial bone of calcium sulphate were applied to fill the cavity and cover the wound in phase I surgical reconstruction after thorough debridement. For the 7 cases with large bone defects or larger cavities after debridement, a mixed bone grafts of antibiotics-loaded artificial bone of calcium sulphate and autologous iliac bone were employed, with muscle flaps or myocutaneous flaps for an embedding repair. Sizes of the tissue flaps were 2.0 cm×3.5 cm to 12.0 cm×23.0 cm. Clinical outcomes were evaluated through follow-ups at outpatient clinic. The therapeutic effect was evaluated by the method described by McKee et al.Results:Except for 1 case of distal necrosis of tissue flap and survived after dressing change, the other tissue flap survived successfully. Postoperative follow-ups lasted for 12 to 40(mean 18) months. All the osteomyelitis were successfully cured, except 1 that had recurrence of osteomyelitis 1 year later, and treated with antibiotics-loaded artificial bone of calcium sulphate combined with autologous iliac bone implants after thorough debridement, and then healed well. The shape and texture of flaps were good. Protective sensations were restored to vary levels after 6 months. The calf regained weight-bearing and walking functions at 1 year after surgery. According to McKee et al., the therapeutic effect was evaluated: 11 cases were cured, 4 cases were improved, and 1 case relapsed, with an effective rate of 93.8%.Conclusion:Application of calf tissue flap combined with antibiotics-loaded artificial bone of calcium sulphate in the treatment of tibia osteomyelitis has a high cure rate and remarkable efficacy. It can significantly reduce the number of surgeries and shorten the course of disease.

Objective:To investigate the efficacy of venetoclax-based combined regimen in treatment of adult patients with acute myeloid leukemia (AML).Methods:The data of 50 adult AML (non-acute promyelocytic leukemia) who received venetoclax-based combined regimen in the First Affiliated Hospital of Xiamen University, Dongguan People's Hospital, the First Hospital of Longyan City, Jieyang People's Hospital from December 2018 to May 2021 were retrospectively analyzed. Different doses venetoclax combined with demethylation drugs or low-dose chemotherapy regimen were used to analyze the therapeutic efficacy. The related factors influencing efficacy were analyzed by using logistic regression.Results:The composite complete remission (CR) rate of 50 AML patients was 62.0% (31/50), the overall response rate (ORR) was 76.0% (38/50); 28 patients achieved effectiveness [CR and partial remission (PR)] after the first cycle and could achieve effectiveness by 3 courses of treatment at the latest. Among 50 patients, 28 cases were newly diagnosed AML, the composite CR rate was 60.8% (17/28), ORR was 78.6% (22/28); 22 cases were recurrent and relapsed, the composite CR rate was 63.6% (14/22), ORR was 72.7% (16/22); and there was no statistically significant difference of ORR between the both groups ( χ2 = 0.23, P = 0.743). Logistic regression multivariate analysis showed age was the only independent influencing factor for the treatment effectiveness ( OR = 8.451, 95% CI 1.306-54.697, P = 0.025). The median duration time of patients receiving venetoclax treatment regimen was 4.5 months (1.1-15.0 months); 16 cases who had treatment effectiveness finally relapsed, the median time of maintaining effectiveness was 5 months (1.1-11.0 months). Additionally, the common treatment-related adverse reactions included bone marrow suppression after treatment, followed by some gastrointestinal reactions like nausea, vomiting and stomachache. In addition, no patient stopped medication for more than 1 week due to bone marrow suppression related complications. Conclusion:Venetoclax-based combined regimen shows a good short-term efficacy in treatment of AML. It is also effective and tolerable for elderly patients receiving reduced dose therapy.

OBJECTIVE：To understand the current status of clinical understanding of “prohibiting”“avoiding”“using caution ” in the application of TCM ，and to provide reference for standardizing the connotation and rational application of “prohibiting” “avoiding”“using caution ”of TCM. METHODS ：Based on the theory of “knowledge-attitude-behavior”，doctor-pharmacist questionnaires and patient questionnaires were designed on the basis of literature research and clinical practice. Through the “Tencent questionnaire ”platform，800 doctor-pharmacist questionnaires were distributed to nearly 300 medical institutions from 32 provinces（cities，autonomous regions ）and 800 patient questionnaires were distributed to public patiants who had used TCM nationwide by anonymous online method. After dimensionality reduction of the questionnaire from three dimensions of cognition ， attention and behavior ，the cognition ，attention and behavior of “prohibiting”“avoiding”“using caution ”in the application of TCM were evaluated by 10 points system. RESULTS ：A total of 703 doctor-pharmacist questionnaires were collected ，including 638 valid questionnaires with recovery rate of 87.9％ and effective rate of 90.8％；Cronbach alpha coefficient was 0.90. A total of 644 patient questionnaires were collected ，including 621 valid questionnaires with recovery rate of 80.5％ and effective rate of 96.4％ . The cognition score of doctors and pharmacists to the terms of “prohibiting”“avoiding”“using caution ”in clinical application of TCM was （7.94±1.21），and that of patients was （5.64±1.54）. The score of doctors and pharmacists ’attention to the above terms was （9.47±1.15）（Spearman Rho correlation coefficient with cognition score was 0.077，P＞0.05），and the score of behavioral ability of patients was （7.01±1.71）（Spearman Rho correlation coefficient with cognition score was －0.021，P＞ 0.05）. The score of behavior ability was （7.43 ± 1.72） （Spearman Rho correlation coefficient with cognition score was 0.233，P＜0.01）. TCM textbooks （89.2％），trainingmeetings （66.5％） and herbal prescriptions （58.2％） were the main ways for doctors and pharmacists to learn the above taboos. Medical staff （74.2％）and internet （52.5％）were the main ways for patients to understand the above taboos. CONCLUSIONS ：Doctors，pharmacists and patients pay more attention to the terms of “prohibiting”“avoiding”“using caution ”in the clinical application of TCM ，but their cognition and executive power were low. Clinical cognition of “prohibiting”“avoiding”“using caution ”in the application of TCM is relatively vague，and the corresponding clinical practice behavior is lacking. It is yet to establish clinical specialist consensus in the field of TCM and publicize it actively to improve the level of clinical rational drug use.

Objective:To investigate the association of plasma epoxyeicosatrienoic acids (EETs) with early neurological deterioration (END), and whether EETs are mediated by EPHX2 gene variants in patients with minor ischemic stroke (MIS).Methods:This is a prospective, multi-center observational study in patients with acute MIS in the Chinese population. Acute MIS patients with the first onset and onset within 24 hours who were admitted to Deyang People′s Hospital, the Second Affiliated Hospital of Wenzhou Medical University and the Third Affiliated Hospital of Wenzhou Medical University from March 2013 to June 2015 were recruited. Plasma EETs levels were measured on admission. Single nucleotide polymorphisms of EPHX2 gene rs751141 were genotyped using mass spectrometry. The primary outcome was END within 10 days after admission. END was defined as an increase in National Institutes of Health Stroke Scale score of 2 or more points.Results:A total of 322 patients were enrolled, of which 85 (26.4%) patients experienced END. EETs levels were significantly lower in patients with END [(60.3±7.3) nmol/L] compared to patients without END [(68.4±8.1) nmol/L , t=8.464, P<0.001]. Frequency of EPHX2 gene rs751141 GG was higher in patients with END [66/85(77.6%)] than in patients without END [123/237(51.9%),χ2=17.130, P<0.001], and patients with EPHX2 gene rs751141 GG genotype showed lower EETs levels [GG: (59.6±7.8) nmol/L, AG:(67.9±8.2) nmol/L, AA:(68.8±3.2) nmol/L, F=9.285, P<0.001]. Low level (≤64.3 nmol/L) of EETs was an independent predictor of END (31.5-51.3 nmol/L group: OR=2.96,95% CI 1.18-8.77, P=0.02; 51.4-64.3 nmol/L group: OR=2.46,95% CI 1.06-6.89, P=0.03) in multivariate analyses. END was associated with a higher risk of poor outcome (modified Rankin Scale scores 3-6) at 3 months ( OR=1.82,95% CI 1.46-2.35, P=0.02). Conclusion:END is fairly common and associated with poor outcomes in acute MIS. EPHX2 gene variants may mediate EETs levels, and low levels of EETs are related to END in acute MIS.

Objective:To compare the embedding anastomosis with the intermittent eversion anastomosis on the pancreatic fistula rates after laparoscopic pancreaticoduodenectomy (LPD).Methods:The clinical data of 116 patients who underwent LPD at the Center Hospital of Xianyang City affiliated to Xi' an Jiaotong University Health Science Center from March 2016 to March 2020 were retrospectively studied. According to the method of pancreaticojejunostomy used, these patients were divided into the following two groups: the embedding anastomosis group ( n=55) and the intermittent eversion anastomosis group ( n=61). The duration of pancreaticojejunostomy, bilioenterostomy and gastrointestinal anastomoses, and the amounts of intraoperative blood loss and postoperative complication rates were compared between the two groups. Results:Of 116 patients in this study, there were 67 males and 49 females, with a median age of 61.5 years. No perioperative death occurred in the 2 groups. The operation time, digestive tract reconstruction time and pancreaticojejunostomy time in the embedded anastomosis group were (260±20), (65±15) and (35±15) min, respectively, which were significantly lower than those in the intermittent eversion anastomosis group (305±25), (81±25) and (45±12) min, (all P<0.05). The grade A and B pancreatic fistula rates in the embedded anastomosis group were 27.3%(15/55) and 21.8%(12/55), respectively, which were significantly higher than those in the intermittent eversion anastomosis group [8.2%(5/61) and 6.6%(4/61)], (all P<0.05). The postoperative hospital stay in the intermittent eversion anastomosis group (10.3±1.1) d was significantly lower than that in the embedding anastomosis group [(15.2±3.2) d, P<0.05]. Conclusion:In LPD, when compared with embedded pancreaticojejunostomy, intermittent eversion pancreaticojejunostomy reduced the postoperative pancreatic fistula rate and shortened the postoperative hospital stay.