Endosomes are characterized by the presence of various phosphoinositides that are essential for defining the membrane properties. However, the interplay between endosomal phosphoinositides metabolism and innate immunity is yet to be fully understood. Here, our findings highlight the evolutionary continuity of RAB-10/Rab10's involvement in regulating innate immunity. Upon infection of Caenorhabditis elegans with Pseudomonas aeruginosa, an increase in RAB-10 activity was observed in the intestine. Conversely, when RAB-10 was absent, the intestinal diacylglycerols (DAGs) decreased, and the animal's response to the pathogen was impaired. Further research revealed that UNC-16/JIP3 acts as an RAB-10 effector, facilitating the recruitment of phospholipase EGL-8 to endosomes. This leads to a decrease in endosomal phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and an elevation of DAGs, as well as the activation of the PMK-1/p38 MAPK innate immune pathway. It is noteworthy that the dimerization of UNC-16 is a prerequisite for its interaction with RAB-10(GTP) and the recruitment of EGL-8. Moreover, we ascertained that the rise in RAB-10 activity, due to infection, was attributed to the augmented expression of LET-413/Erbin, and the nuclear receptor NHR-25/NR5A1/2 was determined to be indispensable for this increase. Hence, this study illuminates the significance of endosomal PI(4,5)P2 catabolism in boosting innate immunity and outlines an NHR-25-mediated mechanism for pathogen detection in intestinal epithelia.
Animals ; Caenorhabditis elegans/genetics* ; Endosomes/immunology* ; Caenorhabditis elegans Proteins/immunology* ; Phosphatidylinositol 4,5-Diphosphate/immunology* ; Immunity, Innate ; Pseudomonas aeruginosa/immunology* ; rab GTP-Binding Proteins/genetics* ; Diglycerides/metabolism*

Objective:To investigate the knowledge of Sixth Chinese national consensus report on the management of Helicobacter pylori infection ( treatment excluded) (hereinafter referred to as sixth national consensus) and 2022 Chinese national clinical practice guideline on Helicobacter pylori eradication treatment (hereinafter referred to as the guideline)among medical staff from general hospitals in Hainan. Methods:From February 20 to May 7, 2023, a questionnaire survey on the diagnosis and treatment of Helicobacter pylori ( H. pylori) infection was conducted among 1 463 medical staff from 15 general hospitals in Hainan Province. The questionnaire was drawn up according to the sixth national consensus and the guideline, covering knowledge of 6 sections, induding H. pylori related diseases, detection of H. pylori, eradication, prevention and influence factors of eradication of H. pylori, etc. Chi-square test was used for statistical analysis. Results:A total of 1 463 valid questionnaires were collected with the effective responsive rate of 100.00%.The 1 463 subjects included 225 gastroenterologists and 1 238 other medical staff(including 503 physicians from other departments, 264 surgeons and 471 medical technologists and pharmacists). About 78.67%(177/225)of gastroenterologists agreed that the overall infection rate of H. pylori in China was more than 20%, the awareness rate was higher than that of other medical staff (physicians from other departments 65.41%(329/503), surgeons 61.74%(163/264), medical technologists and pharmacists 60.30%(284/471); the following datas were sorted by this position), and the difference was statistically significant ( χ2=30.97, P<0.001). About 51.11%(115/225) of gastroenterologists considered that H. pylori serological antibody test could not be used as a diagnostic method for current infection, the awareness rate was higher than that of other medical staff(22.07%(111/503), 14.02%(37/264), 12.31%(58/471)), and the difference was statistically significant( χ2 =152.66, P<0.001). Proton pump inhibitor and potassium-competitive acid blocker should be discontinued for 2 weeks, and antibiotics and bismuth should be discontinued for 4 weeks before urea breath test, and the awareness rates of gastroenterologists were higher than those of other medical staff (38.67%(87/225) vs. 23.26%(117/503), 19.70%(52/264), 18.47%(87/471); 60.89%(137/225) vs. 26.64%(134/503), 25.76%(68/264), 23.78%(112/471)), and the differences were statistically significant ( χ2 =133.70 and 165.51, both P<0.001). For refractory H. pylori infection, 98.67%(222/225)of gastroenterologists agreed with the individualized diagnosis and treatment of H. pylori infection should be guided by bacterial culture, antibiotic susceptibility test or drug resistance gene test, and the awareness rate was higher than that of other medical staff (91.85%(462/503), 93.56%(247/264), 93.21%(439/471)), and the difference was statistically significant( χ2=20.55, P=0.002). About 70.67% (159/225) of gastroenterologists recommended a bismuth containing quadruple regimen, 80.44% (181/225) supported a 10 to 14 day H. pylori eradication course, and the awareness rates were higher than other medical staff (46.92%(236/503), 33.33%(88/264), 32.91%(155/471); 67.20%(338/503), 59.09%(156/264), 53.93%(254/471)), and the differences were statistically significant ( χ2=111.25 and 59.99, both P<0.001). The understanding rates of the sixth national consensus and the guideline in gastroenterologists was 85.33% (192/225), which was higher than that of other medical staff (64.21%(323/503), 66.67%(176/264), 57.96%(273/471)), and the difference was statistically significant ( χ2=85.47, P<0.001). Conclusions:Gastroenterologists from general hospitals in Hainan Province have a better understanding of the sixth national consensus and the guideline than other medical staff. However, there is still a lack of deep understanding of the sixth national consensus and the guideline, and it is necessary to further strengthen the learning and application of the sixth national consensus and the guideline.

Objective To investigate the correlation between baseline data,early treatment response and prognosis in children with acute lymphoblastic leukemia(ALL).Methods Ninety-two children with ALL were divided into the endpoint event group(19 cases)and the event-free survival group(73 cases)according to whether there was an endpoint event(recurrence or death).The age and gender at initial diagnosis were recorded.Initial white blood cell count(WBC),platelet count(PLT),immunophenotype,chromosome karyotype,fusion gene,prednisone test,bone marrow remission status on the 15th day of induction chemotherapy and minimal residual disease(MRD)on the 15th,33rd and 55th day of induction chemotherapy were detected.The correlation between the above baseline data and early treatment response and the occurrence of endpoint event in children with ALL was analyzed.Logistic regression was used to analyze influencing factors of endpoint events in children with ALL.Receiver operating characteristic(ROC)curve was plotted to evaluate the predictive value of baseline data and early treatment response to endpoint events in children with ALL.Results The proportion of WBC≥100×109/L at first diagnosis,prednisone poor reaction and positive MRD on the 33rd day of induction chemotherapy were higher in the endpoint event group than those in the event-free survival group(P<0.05),and there were no significance differences in remaining indicators(P>0.05).Logistic regression analysis showed that prednisone poor reaction and positive MRD on the 33rd day of induction chemotherapy were risk factors for endpoint event in children with ALL(P<0.05),and the combined value of the two indicators was better than that of a single indicator in predicting endpoint events in children with ALL.Conclusion Prednisone poor reaction and positive MRD on the 33rd day of induction chemotherapy are associated with recurrence and death in children with ALL.

The tiered medical treatment system stands as a cornerstone in the deepening reforms of China′s medical and health sectors, playing a crucial role in building a healthy China. Exploring the harmonious coexistence mechanism of multiple entities on the supply and demand sides of the tiered diagnosis and treatment system, and promoting the formation of a scientific and reasonable tiered diagnosis and treatment order, has become an urgent public proposition that needs to be answered and has significant social impact. Addressing the challenges in China′s tiered medical treatment system, particularly its need for a more systematic, comprehensive, and collaborative approach, this study is informed by a thorough literature review. Based on the harmonious management and symbiosis theories, the authors proposed a theoretical concept and future research path for the formation of a harmonious symbiotic mechanism in the tiered diagnosis and treatment system, in order to pave the way for exploring the harmonious symbiotic mechanism in the tiered diagnosis and treatment system.

Purpose: Reduced quality of life after cystectomy has made bladder preservation a popular research topic for muscle-invasive bladder cancer (MIBC). Previous research has indicated significant tumor downstaging after neoadjuvant chemotherapy (NAC). However, maximal transurethral resection of bladder tumor (TURBT) was performed before NAC to define the pathology, impacting the real evaluation of NAC. This research aimed to assess real NAC efficacy without interference from TURBT and apply combined modality therapies guided by NAC efficacy. Materials and Methods: Patients with cT2-4aN0M0 MIBC were confirmed by cystoscopic biopsy and imaging. NAC efficacy was assessed by imaging, urine cytology, and cystoscopy with multidisciplinary team discussion. Definite responders (≤ T1) underwent TURBT plus concurrent chemoradiotherapy. Incomplete responders underwent radical cystectomy or partial cystectomy if feasible. The primary endpoint was the bladder preservation rate. Results: Fifty-nine patients were enrolled, and the median age was 63 years. Patients with cT3-4 accounted for 75%. The median number of NAC cycles was three. Definite responders were 52.5%. The complete response (CR) was 10.2%, and 59.3% of patients received bladder-sparing treatments. With a median follow-up of 44.6 months, the 3-year overall survival (OS) was 72.8%. Three-year OS and relapse-free survival were 88.4% and 60.0% in the bladder-sparing group but only 74.3% and 37.5% in the cystectomy group. The evaluations of preserved bladder function were satisfactory. Conclusion After stratifying MIBC patients by NAC efficacy, definite responders achieved a satisfactory bladder-sparing rate, prognosis, and bladder function. The CR rate reflected the real NAC efficacy for MIBC. This therapy is worth verifying through multicenter research.

In November 4, 2016, a 1 year and 3 months old male patient with face and neck scald complicated with severe scald of oropharynx was admitted to Guangzhou Red Cross Hospital 1 hour after injury. The child developed upper respiratory tract obstruction 2 hours after injury, therefore tracheotomy and intubation were performed immediately to establish an artificial airway, and symptomatic treatments such as anti-infection, fluid replacement, and dressing change were conducted. On the 10th day after injury, the child had difficult breathing during the test tube blocking before extubation, and it was difficult to extubate. Symptomatic treatments such as ventilator assisted ventilation and strengthened anti-infection were continued. On the 17th day after injury, extubation plan was adjusted. Thirty minutes before extubation, phenobarbital was injected intramuscularly for sedation, and atropine was used to reduce airway secretions, after which extubation was successful. After 21 days of treatment, the child was cured and discharged. In the treatment of this case, high attention was paid to the important influence of children′s mental factors among causes of difficult extubation, which provided a reference for clinical treatment of extubation in children with tracheal tube after tracheotomy.

Objective To investigate the dose of docetaxel appropriate for patients with metastatic castration-resistant prostate cancer and its affects to the prognosis.Methods A retrospective analysis was performed on the clinical data of 75 patients with metastatic castration-resistant prostate cancer admitted from March 2010 to July 2016 who received docetaxel combined with prednisone chemotherapy.The patients were divided into the low-dose group (n =43,docetaxel ＜ 65 mg/m2),the middle-dose group (n =21,docetaxel 65-70 mg/m2) and the high-dose group (n =11,docetaxel ＞ 70 mg/m2).The median age in the low-dose group,middle-dose group and high-dose group was 67 (53-80),66 (56-78) and 61 (47-76) years old,respectively.Among 75 patients with bone metastasis,2 patients had no evidence of bone metastasis in the low-dose group.The lymph node metastasis was found in 26,13 and 6 cases in each group,respectively.And visceral and other metastasis were founded in 11,4 and 2 cases,respectively.The Gleason score in the low-dose group was≤7 points in 15 cases,≥8 points in 22 cases and no score in 6 cases.The Gleason score inthe middle-dose group was ≤7 points in 4 cases,≥8 points in 13 cases and no score in 4 cases.The Gleason score in the high-dose group was ≤7 points in 3 cases,≥8 points in 5 cases and no score in 3 cases.The number of patients with pain in the low-dose group,middle-dose group and high-dose group was 36,12 and 9,respectively,there were no significant differences in the above indicators (P ＞ 0.05),except age,which showed relatively more aged patients in the low-dose group,(P =0.045).Kaplan-Meier method was used to compare the overall survival (OS),progression-free survival (PFS) and the incidence of ≥CTCAE-4 grade 3 adverse reactions between the two groups.The Cox regression model was adopted to analyzed the factors that might affect patient prognosis,including the effective time of first-line endocrine therapy,hemoglobin level,ECOG score,pain score,number of cycles of chemotherapy,age,dose of docetaxel and alkaline phosphatase (ALP).Kaplan-Meier method was used to analyze the effect of dose of docetaxel on the prognosis,and log-rank method was used to test the significance of the results.Results The median OS was respectively 24.1,18.5 and 23.5 months in the low-dose group,middle-dose group and high-dose group,respectively.The median PFS was 5.3 months in all three groups,which didn't show statistically significant differences.The incidence of grade 3/4 adverse reactions in the low-dose group,middle-dose group and high-dose group was 15 cases (34.9％),8 cases (38.1％) and 5 cases (45.5％) respectively.It showed an increasing trend,but no statistically significant difference.The single factors related to OS mainly include the effective time of first-line endocrine therapy,hemoglobin level,ECOG score,pain score,number of cycles of chemotherapy,there was no significant correlation with age,docetaxel dose,ALP and PSA value.Conclusions It is common to receive lower doses of docetaxel in clinical practice for patients with metastatic castration-resistant prostate cancer in China.The efficacy of low-dose docetaxel is similar to that of high doses (standard dosage).There was no significant correlation between the OS and the actual dose of docetaxel in the tolerable range.

Objective: To analyze the causes of complication of early acute kidney injury (AKI) in four severely burned patients, and to explore the related treatment methods. Methods: The clinical data of 4 patients with severe burn complicated with early AKI admitted to Guangzhou Red Cross Hospital Affiliated to Medical College of Jinan University (hereinafter referred to as our hospital) from June 2014 to December 2017 were retrospectively analyzed. All the patients were male, aged 23-33 (30±5) years old, with depth of burns ranged from deep partial-thickness to full-thickness, complicated with myofascial compartment syndrome of extremities and varying degrees of striated muscle injury, and treated in other hospitals before transfer to our hospital. The patients were numbered from small to large according to the total burn area. The total burn area of patients No. 1, 2, 3, and 4 was 10%, 80%, 90%, and 95% total body surface area respectively, their occurrence time of early AKI was 48, 11, 29, and 48 hours after injury respectively, and their time of arriving our hospital was 60, 11, 29, and 144 hours after injury respectively. Hypovolemic shock occurred in patients No. 2 and 3 at admission to our hospital. All the patients received continuous renal replacement therapy (CRRT) after admission to our hospital. Under the support of hemodynamic monitoring and organ function monitoring, the limbs complicated with myofascial compartment syndrome were incised, thorough decompression exploration was performed, and necrotic muscle tissue was removed or amputation was performed. After escharectomy and decompression of limbs, fresh granulation wounds were formed by temporarily covering wounds with Jieya dressing skin or pig skin, multiple debridements, and vacuum sealing drainage. Fresh granulation wounds and other wounds underwent staged eschar excision and shaving were covered with autologous Meek skin graft, particulate skin graft, reticular skin graft and small skin graft respectively. The treatment outcome, CRRT time, operation times, time of recovery of serum creatinine and myoglobin, length of hospital stay, and follow-up were recorded. Results: All the 4 patients were cured after transfer to our hospital. Among them, totally 5 limbs of patients No. 1 and No. 4 underwent amputation because of complication of myofascial compartment syndrome and a large amount of necrotic muscle which could not be preserved. Patients No. 1, 2, 3, and 4 were treated with CRRT for 19, 35, 14, and 25 days respectively and performed with operation for 5, 6, 10, 8 times respectively. Serum creatinine of patients No. 1, 2, 3, and 4 returned to normal on 22, 35, 37, and 48 days after transfer respectively, and their serum myoglobin returned to normal on 18, 28, 25, and 30 days after transfer respectively. Patients No. 1, 2, 3, and 4 were hospitalized for 52, 105, 148, and 156 days and discharged after basic wound healing. Follow-up for 1 to 36 months showed no abnormal renal function in 4 patients. Conclusions The early AKI in patients No. 1 and 4 was caused by rhabdomyolysis after severe burn complicated with myofascial compartment syndrome, while that of the other 2 cases were also related to hypovolemic shock and poor renal perfusion. The success rate of early AKI treatment in severely burned patients can be effectively improved by removing the causes of diseases at the same time of CRRT and actively treating burn wounds under the support of organ function and hemodynamic monitoring.

Objective: To investigate the effect and regulatory mechanism of Smurf2 on the negative regulator Smad7 of TGF-β1/Smad signaling pathway in hypertrophic scar fibroblasts. Methods: From January to October 2014, 8 patients with hypertrophic scar after burn were admitted. The age of patients ranged from 1 year 8 months to 7 years, and the time of scar hyperplasia ranged from 2 to 12 months. The residual normal skin of the same patient was used as the control. The fibroblasts were isolated from hypertrophic scar and normal skin respectively and cultured. The third to fifth passage cells were used for the experiments. ① The protein expression of Smad7 in the two groups was detected by Western Blot. ② Hypertrophic scar fibroblasts and normal skin fibroblasts were treated with exogenous TGF-β1 at concentration of 10 ng/ml for 0 min, 5 min, 15 min, 30 min, 1 h, 2 h and 12 h. The expression of Smad7 protein and mRNA were detected by Western Blot and RT-PCR, respectively. ③ The cell lysates of the two groups were collected and incubated with the ubiquitin mixture for 1 h, 2 h and 6 h at 37℃, respectively. The degradation level of Smad7 protein was detected by Western Blot. ④ The cell lysate of hypertrophic scar fibroblasts was collected and incubated with ubiquitin mixture with or without proteasome inhibitor (MG132: MG115=1: 1) to study its inhibitory effect on the degradation of Smad7 in vitro. ⑤ Immunoprecipitation (IP) technique was used to detect the interaction between Smad 7 and E3 ubiquitin ligase Smurf2 in hypertrophic scar fibroblasts. ⑥ The expression of Smad7 protein in hypertrophic scar fibroblasts stimulated by TGF-β1 after Smurf2 silencing by small interference RNA (siRNA) technique were detected by Western blot. Results: ① There was no significant difference in the expression level of Smad7 protein between hypertrophic scar and normal skin fibroblasts(t=0.76, P=0.46). ② Expressions of Smad7 mRNA and protein in normal skin fibroblasts stimulated by exogenous TGF-β1 gradually increased in a time-dependent manner(P<0.05). The expression of Smad7 mRNA in the hypertrophic scar fibroblasts increased at all-time points except at 5min , (P<0.05), while there was no significant difference in the expression level of Smad7 protein at all-time points with or without TGF-β1 stimulation(P>0.05). ③ Degradation of Smad7 protein was enhanced in hypertrophic scar fibroblasts (the expression level of Smad 7 protein at each time point was compared with that of the control group and the last time point, P<0.05), while there was no significant difference in Smad7 protein degradation in normal skin fibroblasts(P=0.162). ④ Enhanced degradation of Smad7 in hypertrophic scar fibroblasts was blocked by the addition of the proteasome inhibitors MG132/MG115. ⑤ In hypertrophic scar fibroblasts, the Smurf2-Smad7 complex was detected, which indicated the interaction between Smurf2 and Smad7 in hypertrophic scar fibroblasts. ⑥ The expression of Smad7 protein was not increased in the hypertrophic scar fibroblasts stimulated by TGF-β1, whereas the stimulation of TGF-β1 increased the expression of Smad7 protein after silencing of Smurf2 gene expression. Conclusions In the hypertrophic scar fibroblasts, Smurf 2 attenuates the inhibitory effect of Smad 7 on TGF-β1 signaling pathway through the degradation of Smad7 by ubiquitination, which may be involved in the formation of hypertrophic scar.

Objective To evaluate the efficacy and safety of the modified docetaxel plus prednisone scheme for the metastatic castration resistant prostate cancer patients who got poor tolerance to chemotherapy.Method The clinical data of 50 metastatic castration resistant prostate cancer who received docetaxel + prednisone chemotherapy from March 2010 to October 2015 were analyzed retrospectively.23 cases received the modified DP regimen (modified group),27 cases received the standard DP regimen (standard group).The median age of the modified group and the standard group were 69 years (47-80 years) and 63 years (52-77 years) (P =0.005).There were 19 and 24 cases with pain in modified group and standard group respectively;10 and 19 cases with lymph node metastasis respectively;3 and 4 cases of visceral metastasis respectively;all of the 50 patients were complicated with bone metastasis.For the pathological Gleason score,there were 7 cases scored ≤7 points,13 cases scored ≥ 8 points and 3 cases unscored in the modified group;7 cases scored ≤7 points,15 cases scored ≥8 points and 5 cases unscored in standard group.There was no significant difference of the pain,metastasis,and Gleason score between the two groups (P ＞ 0.05).Progression free survival (PFS),overall survival (OS)and adverse events were analyzed using Kaplan-Meier curves,and the differences were assessed using the log-rank test.Results In the modified group and standard group,the median follow-up times were 11.0 months and 14.0 months respectively,the median chemotherapy cycles were 4.5 cycles and 5.0 cycles respectively;OS were 18.0 months and 27.5 months respectively (P =0.746).The PFS of the two groups were 6.0 months and 5.2 months,respectively (P =0.822).The PSA response were 13 cases and 17 cases in the modified group and standard group respectively (P =0.615),and the pain response were 8 cases and 7 cases (P =0.927),grade 3 to 4 adverse events were 3 cases and 14 cases (P =0.003).The main adverse events were blood toxicity,neutrophils,gastrointestinal reaction,edema,fatigue and oral mucositis etc.Conclusions Compared with the standard DP scheme,the modified DP scheme had no significant difference in OS,PFS,pain response rate and PSA response rate,while the incidence of grade 3 to 4 adverse events was significantly reduced.Modified DP scheme may be a better choice for patients with metastatic castration resistant prostate cancer who get poor tolerance to chemotherapy.