[Clinical efficacy of induction chemoimmunotherapy for locally advanced hypopharyngeal carcinoma: a prospective phase â ¡ study].

Objective: To evaluate the objective response rate (ORR) of induction chemoimmunotherapy with camrelizumab plus TPF (docetaxel, cisplatin, and capecitabine) for locally advanced hypopharyngeal squamous cell carcinoma (LA HSCC) and potential predictive factors for ORR. Methods: A single-center, prospective, phase 2 and single-arm trial was conducted for evaluating antitumor activity of camrelizumab+TPF(docetaxel+cisplatin+capecitabine) for LA HSCC between May 21, 2021 and April 15, 2023, patients admitted to the Eye & ENT Hospital affiliated with Fudan University. The primary endpoint was ORR, and enrolled patients with LA HSCC at T3-4N0-3M0 received induction chemoimmunotherapy for three cycles: camrelizumab 200 mg day 1, docetaxel 75 mg/m2 day 1, cisplatin 25 mg/m2 days 1-3, and capecitabine 800 mg/m2 days 1-14. Patients were assigned to radioimmunotherapy when they had complete response or partial response (PR)>70% (Group A), or assigned to surgery plus adjuvant radiotherapy/chemoradiotherapy when they had PR≤70% (Group B), and the responses were defined by using tumor volume evaluation system. Tumor diameter was also used to assess the treatment responses by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Use SPSS 23.0 software was used to analyze the data. Results: A total of 51 patients were enrolled who underwent the induced chemoimmunotherapy for three cycles, and all were males, aged 35-69 years old. After three cycles of induction immunochemotherapy, 42 (82.4%) patients existed in Group A (complete response or PR>70%) and 9 patients (17.6%) in Group B (PR≤70%), the ORR was 82.4%. The primary endpoint achieved expected main research objectives. Compared to the patients of Group A, the patients of Group B showed the higher T stage and the larger volume of primary tumor before induced immunochemotherapy, and also had the less regression of tumor volume after induced immunochemotherapy (all P<0.05). The optimal cutoff value of pre-treatment tumor volume for predicting ORR was 39 cm3. The T stage (OR=12.71, 95%CI: 1.4-112.5, P=0.022) and the volume (OR=7.1, 95%CI: 1.4-36.8, P=0.018) of primary tumor were the two main factors affecting ORR rate of induction chemoimmunotherapy. Conclusion: The induction chemoimmunotherapy with camrelizumab plus TPF shows an encouraging antitumor efficacy in LA HSCC.

[The mechanism of NRF2 inhibiting ROS induced autophagy to reduce ovarian granulosa cells damage].

This study explores the effects and possible mechanisms of nuclear factor E2 related factor 2 (NRF2) on ovarian granulosa cells, providing a scientific basis to prevent premature ovarian failure. An ovarian cell injury model was constructed by treating human ovarian granulosa cell (KGN cell) with 4-Vinylcyclohexene dioxide (VCD). Firstly, KGN cells were treated with different concentrations of VCD, and cell counting kit 8 (CCK-8) was used to detect ovarian cell proliferation. After determining IC50 by CCK8, the levels of estradiol and progesterone in the cell supernatant were detected using enzyme-linked immunosorbent assay (ELISA), reactive oxygen species (ROS) assay kit was used to detect the content of ROS in ovarian cells, real-time fluorescence quantitative polymerase chain reaction (qRT PCR) was used to detect the mRNA expression level of NRF2, and Western blot was used to detect the protein expression level of NRF2. Further, NRF2 silence (siNRF2) and overexpression (NRF2-OE) cell models were constructed through lentivirus transfection, and the effects of regulating NRF2 on VCD treated cell models were investigated by detecting hormone levels, oxidative stress indicators (ROS, SOD, GSH-Px), and autophagy (LC3B level). The results showed that VCD intervention inhibited the proliferation of ovarian granulosa cells in a time-dependent and dose-dependent manner (F>100, P<0.05), with an IC50 of 1.2 mmol/L at 24 hours. After VCD treatment, the level of estradiol in the cell supernatant decreased from (56.32±10.18) ng/ml to (24.59±8.75) ng/ml (t=5.78, P<0.05). Progesterone decreased from (50.25±7.03) ng/ml to (25.13±6.67) ng/ml (t=6.54, P<0.05). After VCD treatment, the SOD of cells decreased from (44.47±7.71) ng/ml to (30.92±4.97) ng/ml (t=3.61, P<0.05). GSH-Px decreased from (68.51±10.17) ng/ml to (35.19±6.59) ng/ml (t=5.73, P<0.05). Simultaneously accompanied by an increase in autophagy and a decrease in NRF2. This study successfully constructed KGN cell models that silenced NRF2 and overexpressed NRF2. Subsequently, this study treated each group of cells with VCD and found that the cell proliferation activity of the siNRF2 group was significantly reduced (t=8.37, P<0.05), while NRF2-OE could reverse the cell activity damage caused by VCD (t=3.37, P<0.05). The siNRF2 group had the lowest level of estradiol (t=5.78, P<0.05), while NRF2-OE could reverse the decrease in cellular estradiol levels caused by VCD (t=5.58, P<0.05). The siNRF2 group had the lowest progesterone levels (t=3.02, P<0.05), while NRF2-OE could reverse the decrease in cellular progesterone levels caused by VCD (t=2.41, P<0.05). The ROS level in the siNRF2 group was the highest (t=2.86, P<0.05), NRF2-OE could reverse the increase in ROS caused by VCD (t=3.14, P<0.05), the SOD enzyme content in the siNRF2 group was the lowest (t=2.98, P<0.05), and NRF2-OE could reverse the decrease in SOD enzyme content caused by VCD (t=4.72, P<0.05). The GSH-Px enzyme content in the siNRF2 group was the lowest (t=3.67, P<0.05), and NRF2-OE could reverse the decrease in antioxidant enzyme content caused by VCD (t=2.71, P<0.05). The LC3B level was highest in the siNRF2 group (t=2.45, P<0.05), and NRF2-OE was able to reverse the LC3B elevation caused by VCD (t=9.64, P<0.05). In conclusion, NRF2 inhibits ROS induced autophagy, thereby playing a role in reducing ovarian granulosa cell damage, which may be a potential target for premature ovarian failure.

[Effects of artificial dermis combined with autologous skin in repairing the wounds with exposed bone and/or tendon in fingers of children after electric burns].

Objective: To explore the effects of artificial dermis combined with autologous skin in repairing the wounds with exposed bone and/or tendon in fingers of children after electric burns. Methods: A retrospective observational study was conducted. From January 2017 to December 2022, 14 children with bone and/or tendon exposed wounds in fingers after electric burns who met the inclusion criteria were admitted to Zhengzhou First People's Hospital, including 9 males and 5 females, aged 2 to 11 years. A total of 38 fingers were affected, with 1 wound per finger. After debridement, artificial dermal coverage combined with vacuum sealing drainage was performed in all the wounds in the first stage, with wound area of 2.0 cm×1.0 cm-4.5 cm×2.5 cm after debridement. The second stage surgery was performed to close the wound with autologous thin intermediate thickness skin graft. Then the children were told to perform functional rehabilitation exercise as early as possible. The survival of autologous skin graft was observed at the 7th day after the second stage surgery. The wound healing time was recorded. After 12 months of follow-up, the Vancouver scar scale was used to evaluate the scar hyperplasia at the skin grafting site of the affected finger; the total action mobility (TAM) of the affected finger joint was measured for evaluating the functional recovery of the affected finger; a self-made efficacy satisfaction rating table was used to investigate the parents' satisfaction with the curative effect of the children. Results: At the 7th day after the second stage surgery, all the children had good survival of autologous skin grafts. The wound healing time was (24.1±2.7) d. After 12 months of follow-up, the scar score at the skin grafting site of the affected finger was 5.2±2.4; the TAM of the affected finger joint was (177±40)°; the functional assessment was good in 12 fingers, medium in 23 fingers, and poor in 3 fingers; the parents' satisfaction with the curative effect of the children in the survey was very satisfied in 10 cases, satisfied in 3 cases, and dissatisfied in 1 case. Conclusions: The combination of artificial dermis and autologous thin intermediate thickness skin graft is an alternative surgical method that can effectively repair the bone and/or tendon exposed wounds in fingers of children after electric burns. After wound healing, the scars are slight, the finger function is well recovered, and the parents of the children are highly satisfied with the curative effect of the children, which is worthy of clinical promotion.

[Effects of rapid drug sensitivity testing for multidrug-resistant bacteria on the prognosis of patients with severe intra-abdominal infection].

Objective: To examine the clinical value of rapid detection of drug-resistant bacteria by immunochromatography and the effects of rapid detection on the prognosis of patients with severe intra-abdominal infection complicated by carbapenem-resistant Enterobacteriaceae (CRE) bloodstream infection. Methods: This was a retrospective cohort study. We analyzed clinical data of 73 patients with severe abdominal infections with sepsis or septic shock complicated by CRE bloodstream infection admitted to the general surgery department of Jinling Hospital between February 2022 and February 2023. Patients were divided into a colloidal gold immunochromatographic assay (GICA) group (17 patients) and conventional testing group (56 patients) based on whether a GICA for CRE had been performed on the patients' first blood culture sample during the diagnosis and treatment process. There were no statistically significant differences between the GICA and conventional testing groups in age ([55.9±17.3] vs. [47.6±16.4] years), sex ([16 men vs. one woman ] vs. [41 men vs. 15 women]), median Charlson comorbidity index (3.0[2.0,4.0] vs. 3.0[2.0, 4.8]), septic shock (10 vs. 39), or acute kidney injury (8 vs. 40) (all P>0.05). Both groups routinely underwent traditional bacterial identification and drug susceptibility testing. Additionally, patients in the GICA group were tested directly for positive blood cultures using a GICA carbapenemase test kit. The main outcomes were mortality rates on Days 28 and 90 after the first identification of CRE bloodstream infection in both groups. We also compared the microbial clearance rate, duration of hospitalization and intensive care unit stay, and time from onset of CRE bloodstream infection to initiation of targeted and appropriate antibiotics between the two groups. Results: The rate of microbial clearance of bloodstream infection was significantly greater in the GICA group than in the conventional testing group (15/17 vs. 34/56 [60.7%], χ2=4.476, P=0.034), whereas the 28-day mortality tended to be lower in the GICA than conventional testing group [5/17 vs. 44.6% [25/56], χ2=1.250, P=0.264). The 90-day mortality (8/17 vs. 53.6% [30/56], χ2=0.222, P=0.638), median duration of hospitalization (37.0 [18.0, 46.5] days vs. 45.5 [32.2, 64.8] days, Z=-1.867, P=0.062), and median duration of intensive care unit stay (18.0 [6.5, 35.0] days vs. 32.0 [5.0, 51.8] days, Z=-1.251, P=0.209). The median time between the onset of bloodstream infection and administration of antibiotics was 49.0 (38.0, 69.0) hours in the GICA group, which is significantly shorter than the 163.0 (111.8, 190.0) hours in the conventional testing group (Z=-5.731, P<0.001). The median time between the onset of bloodstream infection and administration of appropriate antibiotics was 40.0 (34.0, 80.0) hours in the GICA group, which is shorter than in the conventional testing group (68.0 [38.2, 118.8]) hours; however, this difference is not statistically significant (Z=-1.686, P=0.093). Conclusions: GICA can provide information on carbapenemase- producing pathogens faster than traditional drug sensitivity testing, enabling early administration of the optimal antibiotics. The strategy of 'carbapenemase detection first' for managing bacterial infection has the potential to improve prognosis of patients and reduce mortality rate.

Risk prediction of second primary malignancies in primary colorectal neuroendocrine neoplasms patients: a population-based study.

PURPOSE: In this study, we aimed to identify risk factors for developing second primary malignancies (SPMs) in colorectal neuroendocrine neoplasms (NENs) patients and develop a competing-risk nomogram to predict SPMs' probabilities quantitatively. METHODS: Patients with colorectal NENs were retrospectively collected from the Surveillance, Epidemiology, and End Results (SEER) database during 2000-2013. Potential risk factors for SPMs' occurrence in colorectal NENs' patients were identified by the Fine and Gray's proportional sub-distribution hazards model. Then, a competing-risk nomogram was constructed to quantify SPMs' probabilities. The discriminative abilities and calibrations of this competing-risk nomogram were assessed by the area under the receiver-operating characteristic (ROC) curves (AUC) and calibration curves. RESULTS: We identified 11,017 colorectal NENs' patients, and randomly divided them into training (n = 7711 patients) and validation (n = 3306 patients) cohorts. In the whole cohort, 12.4% patients (n = 1369) had developed SPMs during the maximum follow-up of approximately 19 years (median 8.9 years). Sex, age, race, primary tumor location, and chemotherapy were identified as risk factors for SPMs' occurrence in colorectal NENs' patients. Such factors were selected to develop a competing-risk nomogram and showed excellent predictive ability for SPMs' occurrence (the 3-, 5-, and 10-year AUC values were 0.631, 0.632, and 0.629 in the training cohort and 0.665, 0.639, 0.624 in the validation cohort, respectively). CONCLUSIONS: This research identified risk factors for SPMs' occurrence in colorectal NENs' patients. Competing-risk nomogram was constructed and proved to have good performance.

[Clinicopathological characteristics of Klinefelter syndrome: a testicular biopsy analysis of 87 cases].

Objective: To investigate the clinicopathological characteristics of testicular biopsies from Klinefelter syndrome (KS) patients. Methods: The testicular biopsy specimens of 87 patients with KS (a total of 107 biopsy specimens) were collected from the Department of Pathology, Peking University Third Hospital, Beijing, China from January 2017 to July 2022. All patients were diagnosed as KS by peripheral blood karyotyping analysis. The testicular histopathologic features, testicular volume and hormone levels were evaluated retrospectively. The histopathologic analysis was used to assess the quantity and morphology of Leydig cells, the spermatogenic state of seminiferous tubules, the thickening of the basement membrane of seminiferous tubules and the changes of stroma. Results: Leydig cell proliferative nodules were seen in 95.3% (102/107) of KS testicular biopsy tissues. The eosinophilic inclusion bodies and lipofuscin in Leydig cells were found in 52.3% (56/107) and 57.9% (62/107) of specimens, respectively. The Sertoli cell only seminiferous tubules and the hyalinized tubules were found in 66.4% (71/107) and 76.6% (82/107) of the examined tissues, respectively. The tubules with complete spermatogenic arrest were found in 15.9% (17/107) of specimens, and 5.6% (6/107) of the specimens showed low spermatogenesis or incomplete spermatogenic arrest. In 85.0% (91/107) of the specimens, increased thick-walled small vessels with hyaline degeneration were identified. Conclusions: The most common features of KS testicular specimens are Leydig cell proliferative nodules, hyaline degeneration of seminiferous tubules and proliferation of thick-walled blood vessels. Testicular biopsy specimens of KS are rare. The pathologists can make a tentative diagnosis of KS based on the histological findings, combined with the ultrasound and laboratory results, which is helpful for further diagnosis and treatment of KS.

[Validation of calculation method for dose distribution around radioactive iodine-125 particles based on AAPM TG43 report].

Objective: According to the formula provided by the TG43 report [AAPM TG43 (2004)] proposed by the American Association of Physicists in Medicine (AAPM) in 2004, we calculated the dose distribution around the radioactive iodine-125 particles, and verified the calculation accuracy of the radioactive iodine-125 particles treatment planning system. Methods: AAPM TG43 (2004) report provides two calculation methods when calculating the dose around a single radioactive source. The calculation method that does not consider the geometric structure of the radioactive source is called point source calculation method, and the calculation method that considers the geometric structure of the radioactive source is called line source calculation method. Assuming a single Amersham 6711 radioactive iodine-125 particle with an activity of 100 U, the following point doses were calculated according to the two calculation methods provided by AAPM TG43 (2004) report, at 0°, 90° directions, distances 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 and 6 cm; In the direction of 45°, the doses at 0.71, 1.41, 2.12, 2.83, 3.54, 4.24, 4.95, 5.66, 6.36, 7.07, 7.78 and 8.49 cm. On the clinically used brachytherapy planning system variseeds 8.0, the above two calculation methods are used to calculate the corresponding activity and the dose around the corresponding type of radioactive iodine-125 particles, and the function of capturing points to templates built in the planning system is used to accurately find the above corresponding point position, using a single measurement of the above corresponding point dose; and comparation of the results were performed to see if there is a statistical difference. Results: The AAPM TG43 report uses point source calculation method to calculate the dose of single Amersham 6711 radioactive iodine-125 particles with activity of 100 U at 0° and 90° directions. The points with the same distance and the same dose are 8 082.18, 1 870.08, 756.58, 381.47, 217.11, 131.91, 86.55, 58.32, 39.97, 27.42, 19.74, 14.13 Gy, respectively, at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 and 6 cm away from them. In the 45° direction, the doses at the distances of 0.71, 1.41, 2.12, 2.83, 3.54, 4.24, 4.95, 5.66, 6.36, 7.07, 7.78 and 8.49 cm are 3 957.37, 865.83, 329.99, 155.69, 84.10, 48.50, 28.49, 17.80, 11.37, 7.38, 4.98 and 3.39 Gy, respectively; For line source calculation method, radioactive particles are at the same distance as above. The doses at each point in the direction of 0° are 3 128.71, 755.44, 330.30, 180.53, 107.74, 68.56, 46.40, 32.22, 22.70, 16.00, 11.51, 8.24 Gy, respectively. The doses at each point in the direction of 90° are 8 306.46, 1 981.01, 802.74, 405.38, 230.60, 140.03, 91.83, 61.84, 42.36, 29.05, 20.91, 14.97 Gy; In the 45° direction, the dose at the corresponding distance as above is 4 020.78, 877.43, 333.49, 156.93, 84.69, 48.81, 28.65, 17.89, 11.42, 7.41, 4.99 and 3.40 Gy, respectively. The maximum dose difference (0.3%) between the two methods is 7.78 cm in the 45° direction, the maximum difference (-0.3%) between the two methods is 8.49 cm in the 45° direction, and the value of other sampling points is less than 0.3%. The closer the Amersham 6711 iodine-125 particles are to the source in the directions of 0°, 45°, and 90°, the faster the dose will drop, and the dose will drop gradually as the distance increases. Conclusion: The brachytherapy planning system variseeds 8.0 and the AAPM TG43 report calculate a maximum dose difference of 0.3%, which can accurately calculate the dose distribution around radioactive iodine-125 seeds, and provide a reliable tool for the clinical implementation of radioactive iodine-125 particles implantation for tumor treatment.

[Nur77 promotes invasion and migration of gastric cancer cells through the NF-κB/IL-6 pathway].

OBJECTIVE: To analyze the association of Nur77 with overall survival of gastric cancer patients and investigate the role of Nur77 in invasion and migration of gastric cancer cells. METHODS: Oncomine database was used to analyze the expression of Nur77 in gastric cancer and gastric mucosa tissues, and the distribution characteristics of Nur77 protein between gastric cancer and normal tissues were compared using Human Protein Atlas. GEPIA2 was used to analyze the relationship of Nur77 expression and the patients' survival. The expression of Nur77 in gastric cancer cell lines GES-1, AGS and MKN-45 were detected by Western blotting. The regulatory interactions between IL-6 and Nur77 were verified by transfecting the cells with specific Nur-77 siRNA and Nur-77-overexpressing plasmid. The changes in migration ability of the cells following Nur-77 knockdown were assessed with scratch assay. The effect of Nur-77 overexpression or IL-6 knockdown, or their combination, on migration and invasion of the gastric cancer cells were examined using Transwell assay. The effect of Nur77 expression level on NF-κB/IL-6 pathway activation was analyzed using Western blotting. RESULTS: Oncomine database showed that gastric cancer tissues expressed a significantly higher level of Nur77 mRNA than normal tissues (P < 0.05). Nur77 expression was detected mostly in the nucleus, and a high Nur77 expression was associated with a poor survival outcome of the patients (P < 0.05). In gastric cancer cells, the high expression of Nur77 participated in the regulation of IL-6. Nur77 silencing significantly lowered the migration ability of the cells (P < 0.05), and IL-6 silencing significantly attenuated the enhanced migration caused by Nur77 overexpression (P < 0.05). Nur77 participates in the activation of NF-κB/IL-6 signaling pathway by regulating the expression of p-p65, p65, p-Stat3 and Stat3. CONCLUSION: A high Nur77 expression is strongly correlated with a poor prognosis of gastric cancer patients. Nur77 promotes the invasion and migration of gastric cancer cells possibly by regulating the NF-κB/IL-6 signaling pathway.

[Long-term outcome follow-up of Oxford unicompartmental knee arthroplasty for medial compartment osteoarthropathy:a single center's experience for 10 years].

Objective: To investigate the long-term outcomes of minimally invasive Oxford phase Ⅲ unicompartmental knee arthroplasty (UKA) for patients with medial compartment osteoarthropathy. Methods: The clinical data of 594 patients (701 knees) who underwent minimally invasive UKA with Oxford phase Ⅲ unicompartmental prosthesis at Department of Orthopedics,the Affiliated Hospital of Qingdao University from January 2007 to January 2016 were retrospectively analyzed.There were 155 males and 439 females,aged (62.6±10.9) years (range: 44 to 81 years),with a body mass index of (26.9±3.8) kg/m2 (range: 21.1 to 36.2 kg/m2).There were 359 left knees and 342 right knees,676 knees with osteoarthritis and 25 knees with idiopathic osteonecrosis of the medial femoral condyle.There were 487 cases underwent UKA (66 cases underwent UKA on one side and total knee arthroplasty on the other) and 107 cases underwent bilateral UKA.Patients' prosthetic survival,complications,range of motion(ROM) of the knee,visual analogue score (VAS),Western Ontario and McMaster University (WOMAC) osteoarthritis index,and American knee society score (KSS) were collected to assess clinical outcomes.Paired sample t test was used to compare the data before and after operation. Results: All patients completed the surgery successfully.There was no intraoperative fractures,postoperative infections or symptomatic vascular embolic disease occurred.The postoperative complications,including mobile bearing dislocation,prosthesis loosening,tibial plateau collapse,the lateral compartment degeneration and postoperative pain were occurred in 18 cases (3.0%,18/594).Thirteen patients suffered complications were transferred to total knee arthroplasty,4 underwent partial revision,if this was used as the endpoint of the study,the surgical success rate was 97.1% (577/594) and the prosthetic revision rate was 2.9%.The ROM was improved from(105.9±11.8)°preoperatively to (114.0±13.3)° at the last follow-up (t=10.796,P<0.01);the KSS clinical score was increased from 54.3±3.6 to 90.1±6.0 (P<0.01) and the functional score was increased from 55.9±3.9 to 87.5±5.7(t=124.325,P<0.01;t=110.985,P<0.01).The WOMAC osteoarthritis index was decreased from 54.8±6.7 to 9.2±3.1 at the last follow-up(t=150.860,P<0.01) and the VAS was decreased from 6.1±1.1 to 1.5±1.0 at the last follow-up(t=74.941,P<0.01). Conclusions: Minimally invasive Oxford phase Ⅲ UKA for medial compartment knee osteoarthritis has a favorable prosthesis survival rate,low revision rate,and few complications at long-term follow-up.Patients have significant improvement in knee function with satisfactory clinical outcomes.

Identification and Verification of the Ability of Cdk5 to Phosphorylate Deubiquitinating Enzyme BRCC3 In Vitro.

It is known that the expression of the deubiquitinating enzyme BRCA1-BRCA2-containing complex subunit 3 (BRCC3) and cyclin-dependent protein kinase 5 (Cdk5) is increased in Parkinson's disease (both are involved in neuroinflammatory response). However, the regulatory mechanism of Cdk5 on the post-translational modification of BRCC3 remains unclear. Here we studied whether Cdk5 phosphorylates BRCC3. Phosphorylation of BRCC3 by Cdk5 was predicted by GPS 5.0 software. His-BRCC3 plasmid was constructed by cloning the BRCC3 gene into pGEX-6P-1 vector, and then His-BRCC3 fusion protein was induced with isopropyl ß-d-1-thiogalactopyranoside and purified using His-Tag affinity chromatography purification agarose. Phosphorylation of BRCC3 fusion protein by Cdk5 in vitro was detected by mass spectrometry and Western blotting. The results showed that multiple phosphorylation sites were predicted by GPS 5.0, and the His-BRCC3 fusion protein was successfully induced and purified. In vitro kinase assay, Western blotting, and mass spectrometry showed that Cdk5 can phosphorylate BRCC3. It has been demonstrated that protein kinase Cdk5 can phosphorylate the deubiquitinating enzyme BRCC3 in vitro, which provides new data for further study on the mechanism of neurodegeneration.

[Agkistrodon halys venom antitumor component-I inhibits vasculogenic mimicry in triple-negative breast cancer cells in vitro by down-regulating MMP2].

OBJECTIVE: To investigate the inhibitory effect of agkistrodon halys venom antitumor component-I (AHVAC-I) on vasculogenic mimicry (VM) formation in triple-negative breast cancer MDA-MB-231 cells and explore its possible mechanism. METHODS: CCK8 assay was used to determine the optimal concentration of AHVAC-I for cell treatment based on its halfinhibitory concentration (IC50). MDA-MB-231 cells were treated with different concentrations of AHVAC-I or 5-Fu, and the changes in vasomimetic capacity of the cells were examined using Matrigel assay. The expression levels of matrix metalloproteinase-2 (MMP2) and MMP9 in the treated cells were detected using quantitative PCR and Western blotting. RESULTS: Compared with the control treatment with culture medium, treatment with 5, 10 and 20 µg/mL AHVAC-I significantly reduced vasomimetic ability of MDA-MB-231 cells in a dose-dependent manner (P < 0.01). MMP2 supplementation obviously restored the vasomimetic ability of the cells inhibited by AHVAC-I. CONCLUSION: AHVAC-I inhibits VM formation in triplenegative breast cancer cells in vitro by down-regulating MMP2 production.

[Value of cerebral hypoxic-ischemic injury markers in the early diagnosis of sepsis associated encephalopathy in burn patients with sepsis].

Objective: To explore the value of cerebral hypoxic-ischemic injury markers in the early diagnosis of sepsis associated encephalopathy (SAE) in burn patients with sepsis. Methods: A retrospective case series study was conducted. From October 2018 to May 2021, 41 burn patients with sepsis who were admitted to Zhengzhou First People's Hospital met the inclusion criteria, including 23 males and 18 females, aged 18-65 (35±3) years. According to whether SAE occurred during hospitalization, the patients were divided into SAE group (21 cases) and non-SAE group (20 cases). The gender, age, deep partial-thickness burn area, full-thickness burn area, and acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) scores of patients were compared between the two groups. The serum levels of central nervous system specific protein S100ß and neuron specific enolase (NSE) at 12, 24, and 48 h after sepsis diagnosis (hereinafter referred to as after diagnosis), the serum levels of interleukin-6 (IL-6), IL-10, tumor necrosis factor α (TNF-α), Tau protein, adrenocorticotropic hormone (ACTH), and cortisol at 12, 24, 48, 72, 120, and 168 h after diagnosis, and the mean blood flow velocity of middle cerebral artery (VmMCA), pulsatility index, and cerebral blood flow index (CBFi) on 1, 3, and 7 d after diagnosis of patients in the two groups were counted. Data were statistically analyzed with chi-square test, analysis of variance for repeated measurement, independent sample t test, and Bonferroni correction. The independent variables to predict the occurrence of SAE was screened by multi-factor logistic regression analysis. The receiver operating characteristic (ROC) curve was drawn for predicting the occurrence of SAE in burn patients with sepsis, and the area under the curve (AUC), the best threshold, and the sensitivity and specificity under the best threshold were calculated. Results: The gender, age, deep partial-thickness burn area, full-thickness burn area, and APACHE Ⅱ score of patients in the two groups were all similar (χ2=0.02, with t values of 0.71, 1.59, 0.91, and 1.07, respectively, P>0.05). At 12, 24, and 48 h after diagnosis, the serum levels of S100ß and NSE of patients in SAE group were all significantly higher than those in non-SAE group (with t values of 37.74, 77.84, 44.16, 22.51, 38.76, and 29.31, respectively, P<0.01). At 12, 24, 48, 72, 120, and 168 h after diagnosis, the serum levels of IL-10, Tau protein, and ACTH of patients in SAE group were all significantly higher than those in non-SAE group (with t values of 10.68, 13.50, 10.59, 8.09, 7.17, 4.71, 5.51, 3.20, 3.61, 3.58, 3.28, 4.21, 5.91, 5.66, 4.98, 4.69, 4.78, and 2.97, respectively, P<0.01). At 12, 24, 48, 72, and 120 h after diagnosis, the serum levels of IL-6 and TNF-α of patients in SAE group were all significantly higher than those in non-SAE group (with t values of 8.56, 7.32, 2.08, 2.53, 3.37, 4.44, 5.36, 5.35, 6.85, and 5.15, respectively, P<0.05 or P<0.01). At 12, 24, and 48 h after diagnosis, the serum level of cortisol of patients in SAE group was significantly higher than that in non-SAE group (with t values of 5.44, 5.46, and 3.55, respectively, P<0.01). On 1 d after diagnosis, the VmMCA and CBFi of patients in SAE group were significantly lower than those in non-SAE group (with t values of 2.94 and 2.67, respectively, P<0.05). On 1, 3, and 7 d after diagnosis, the pulsatile index of patients in SAE group was significantly higher than that in non-SAE group (with t values of 2.56, 3.20, and 3.12, respectively, P<0.05 or P<0.01). Serum IL-6 at 12 h after diagnosis, serum Tau protein at 24 h after diagnosis, serum ACTH at 24 h after diagnosis, and serum cortisol at 24 h after diagnosis were the independent risk factors for SAE complicated in burn patients with sepsis (with odds ratios of 2.42, 1.38, 4.29, and 4.19, 95% confidence interval of 1.76-3.82, 1.06-2.45, 1.37-6.68, and 3.32-8.79, respectively, P<0.01). For 41 burn patients with sepsis, the AUC of ROC of serum IL-6 at 12 h after diagnosis for predicting SAE was 0.92 (95% confidence interval was 0.84-1.00), the best threshold was 157 pg/mL, the sensitivity was 81%, and the specificity was 89%. The AUC of ROC of serum Tau protein at 24 h after diagnosis for predicting SAE was 0.92 (95% confidence interval was 0.82-1.00), the best threshold was 6.4 pg/mL, the sensitivity was 97%, and the specificity was 99%. The AUC of ROC of serum ACTH at 24 h after diagnosis for predicting SAE was 0.96 (95% confidence interval was 0.89-1.00), the best threshold was 14.7 pg/mL, the sensitivity was 90%, and the specificity was 94%. The AUC of ROC of serum cortisol at 24 h after diagnosis for predicting SAE was 0.93 (95% confidence interval was 0.86-1.00), the best threshold was 89 nmol/L, the sensitivity was 94%, and the specificity was 97%. Conclusions: Serum Tau protein, ACTH, and cortisol have high clinical diagnostic value for SAE complicated in burn patients with sepsis.

Del-1 enhances therapeutic efficacy of bacterial cancer immunotherapy by blocking recruitment of tumor-infiltrating neutrophils.

BACKGROUND: Bacterial-mediated cancer immunotherapy (BCI) elicits a more robust initial immune response than conventional immunotherapy, but does not prevent tumor recurrence and metastasis. BCI is associated with recruitment of tumor-infiltrating neutrophils, which could suppress the therapeutic efficacy of this modality. Development endothelial locus 1 (Del-1), a potent inhibitor of neutrophil recruitment, antagonizes lymphocyte function-associated antigen-1 on the vascular endothelium. Here, we aimed to determine the effect of Del-1-secreting S.t△ppGpp on anti-tumor activity and tumor-infiltrating neutrophil recruitment in a mouse model of colon cancer. METHODS: We investigated the anti-cancer activity of Del-1-secreting engineered Salmonella (△ppGpp S. Typhimurium) in the mice colon cancer models. RESULTS: In the present study, we identified that Del-1-secreting engineered Salmonella had more potent anti-cancer activity compared with normal S.t△ppGpp without Del-1 secretion. We postulated that Del-1 expression increased M1 macrophage recruitment to tumors by decreasing tumor-infiltrating neutrophils. This approach could enhance the anti-cancer effects of S.t△ppGpp. CONCLUSIONS: Collectively, the approach of using engineered bacteria that deliver Del-1 to block tumor-infiltrating neutrophil recruitment is a potential therapeutic approach.

Production and purification of 2-phenylethanol by Saccharomyces cerevisiae using tobacco waste extract as a substrate.

2-phenylethanol (2-PE), which is extracted naturally from plant or biotechnology processing, is widely used in the food and cosmetics industries. Due to the high cost of 2-PE production, the valorization of waste carbon to produce 2-PE has gained increasing attention. Here, 2-PE was produced by Saccharomyces cerevisiae using tobacco waste extract (TWE) as the substrate. Considering the toxicity of nicotine and its inhibition of 2-PE, the tolerance of S. cerevisiae was first evaluated. The results suggested that the production of 2-PE by S. cerevisiae in TWEs could be carried out at 2·0 mg ml-1 nicotine concentrations and may be inhibited by 1·0 mg ml-1 2-PE. Thus, the compounds in the TWEs prepared at different temperatures were detected, and the results revealed that the TWEs prepared at 140°C contained 2·18 mg ml-1 of nicotine, had total sugar concentrations of 26·8 mg ml-1 and were suitable for 2-PE production. Due to feedback regulation, the 2-PE production was only 1·11 mg ml-1 , and the remaining glucose concentration remained at 13·78 mg ml-1 , which indicated insufficient glucose utilization. Then, in situ product recovery was further implemented to remove this inhibition; the glucose utilization (the remaining concentration decreased to 3·64 mg ml-1 ) increased, and the 2-PE production increased to 1·65 mg ml-1 . The 2-PE produced in the fermentation broth was first isolated by elution from the resin with 75% ethanol and then by removing the impurities with 2·5% activated charcoal, and pure 2-PE was identified by gas chromatography mass spectrometry. The results of this study suggest that TWE could be an alternative carbon source for 2-PE production. This could provide an outlet tobacco waste as well as reducing the price of natural 2-PE, although more strategies need to be explored to improve the production yield of 2-PE by using TWE.

[Effect of laparoscopic novel W-H fundoplication in patients with proton pump inhibitor dependent gastroesophageal reflux disease].

Objective: To investigate the effect of a novel laparoscopic W-H fundoplication in the treatment of proton pump inhibitor (PPI) dependent gastroesophageal reflux disease (GERD). Methods: The clinical data of PPI dependent GERD patients who underwent laparoscopic W-H fundoplication in PLA Rocket Force Characteristic Medical Center from October 1st, 2018 to April 30th, 2019 were analyzed retrospectively. The GERD symptom score, subjective symptom relief, PPI withdrawal, efficacy satisfaction and postoperative complications were followed up and analyzed by a questionnaire. Results: A total of 80 GERD patients were included in this study, and 49 were male and 31 were female, with a median age of 58 years. Among all patients, 85% (68/80) are with esophagitis and 77.5% (62/80) with hiatal hernia. The operation time was 67 (52, 73) minutes, without intraoperative complications and conversion to laparotomy. The postoperative follow-up period was 16 (14, 18) months. The postoperative GERD symptom scores were significantly lower than those before surgery, with an statistical difference (all P<0.05). The subjective remission degree of the overall digestive and respiratory symptoms were 100 (90, 100)% and 100 (80, 100)%, respectively. During the follow-up period, the PPI discontinuation rate was 83% (69/80), and the satisfactory rate was 93% (75/80). Postoperative complications included dysphagia, flatulence, increased exhaust and diarrhea, and the incidence was 61% (49/80), 8% (6/80), 5% (4/80) and 4% (3/80), respectively, and 16% (13/80) of the patients had prolonged occasional mild dysphagia. There was no death, symptomatic recurrence or reoperation. Conclusions: The novel W-H fundoplication has a good medium-term efficacy, with significant GERD symptom control rate and PPI discontinuation rate. The postoperative dysphagia is common, but it is self-limiting and does not affect the satisfaction of the surgical effect.

Diffusion-tensor imaging for differentiating uterine sarcoma from degenerative uterine fibroids.

AIM: To explore the applicability of diffusion-tensor imaging (DTI) sequence quantitative parameters in differentiating uterine sarcoma (USr) from degenerative uterine fibroids (DUF). MATERIALS AND METHODS: Fourteen cases of USr and 30 cases of DUF were analysed retrospectively. The diffusion-weighted imaging (DWI) and DTI images were analysed by two observers using Functool software on a ADW4.6 workstation. The images were post-processed to generate an apparent diffusion coefficient (ADC) map of DWI, ADC map of DTI (ADCT map), and fractional anisotropy (FA) map. Three regions of interest (ROI) were selected from the ADC, ADCT, and FA maps to obtain the ADC, ADCT, and FA values. The receiver operating characteristic (ROC) curves of all parameters were used to analyse and compare the diagnostic value of USr and DUF. RESULTS: The ADC value, ADCT value, and FA value of USr (1.190 ± 0.262 × 10-3mm2/s, 1.165 ± 0.270 × 10-9mm2/s, 0.168 ± 0.063) were significantly lower compared to the values for DUF (1.525 ± 0.314 × 10-3mm2/s, 1.650 ± 0.332 × 10-9mm2/s, 0.254 ± 0.111; all p<0.001). The diagnostic threshold values for USr were: ADC ≤1.290 × 10-3mm2/s, ADCT ≤1.322 × 10-9mm2/s and FA ≤0.192. The corresponding sensitivities and specificities were 78.6%/90%, 96.7%/92.9%, and 86.7%/85.7%, respectively. The areas under the curve (AUC) were 0.875, 0.974, and 0.831, respectively. CONCLUSIONS: DTI quantitative parameters can be used to differentiate USr from DUF. The ADCT value had the highest diagnostic efficacy.

Downregulating long non-coding RNA CCAT5 inhibits tumor growth, invasion and metastasis in colorectal cancer through suppressing STAT3.

Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "Downregulating long non-coding RNA CCAT5 inhibits tumor growth, invasion and metastasis in colorectal cancer through suppressing STAT3, by Y. Wang, X.-L. Yan, S.-K. Tian, published in Eur Rev Med Pharmacol Sci 2019; 23 (18): 7899-7904-DOI: 10.26355/eurrev_201909_19001-PMID: 31599415" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/19001.