Lysobacter harbors a plethora of cryptic biosynthetic gene clusters (BGCs), albeit only a limited number have been analyzed to date. In this study, we described the activation of a cryptic polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) gene cluster (lsh) in Lysobacter sp. DSM 3655 through promoter engineering and heterologous expression in Streptomyces sp. S001. As a result of this methodology, we were able to isolate two novel linear lipopeptides, lysohexaenetides A (1) and B (2), from the recombinant strain S001-lsh. Furthermore, we proposed the biosynthetic pathway for lysohexaenetides and identified LshA as another example of entirely iterative bacterial PKSs. This study highlights the potential of heterologous expression systems in uncovering cryptic biosynthetic pathways in Lysobacter genomes, particularly in the absence of genetic manipulation tools.
Lysobacter/metabolism* ; Streptomyces/metabolism* ; Lipopeptides/metabolism* ; Polyketide Synthases/genetics* ; Multigene Family

Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC₅₀ values and achieved picomolar DC₅₀ values and >99% of maximum degradation (D_max) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15 dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-MET^Y1230H and c-MET^D1228N mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.

Objective:To explore the mediating roles of rumination and avoidance coping between information anxiety and suicidal ideation.Methods:In March 2022, a total of 896 college students were surveyed by the information anxiety scale(IAS), ruminative responses scale(RRS), coping style questionnaire(CSQ)and self-rating idea of suicidal ideation scale(SIOSS). The ANOVA analysis, Pearson correlation analysis and mediating effect analysis were performed by the SPSS 22.0 software.Results:The detection rate of suicidal ideation among college students was 9.15%(82/896). The information anxiety score was(73.84±17.29), the rumination score was(47.73±12.16), the avoidance coping score was(3.76±2.52), and the suicidal ideation score was(5.41±4.09). Information anxiety was significantly positively correlated with rumination, avoidance coping and suicidal ideation( r=0.49, 0.36, 0.37, all P<0.05). Rumination was significantly positively correlated with avoidance coping and suicidal ideation( r=0.42, 0.59, both P<0.05). There was a significantly positive correlation between avoidance coping and suicidal ideation( r=0.45, P<0.05). Information anxiety affected suicidal ideation of college students through four paths.The direct effect value of information anxiety on suicidal ideation was 0.06, accounting for 16.67% of the total effect. The effect values of the separate mediating effect of rumination and avoid coping were 0.22 and 0.04, and accounting for 61.11% and 11.11% of the total effect respectively. The chain mediating effect value of rumination and avoid coping was 0.04, accounting for 11.11% of the total effect. Conclusion:Information anxiety can directly affect suicidal ideation of college students and indirectly affect suicidal ideation through rumination and avoidance coping.

Objective To explore dendritic cells (DCs)-mediated antigen presentation for radiation-injured cells by using the in vitro cell co-culture technology to simulate the in vivo microenvironment of the lung tissue. Methods ⁶⁰Co γ-irradiated mouse lung epithelial cells (MLE-12) were cultured with bone marrow-derived DCs and/or splenic T lymphocytes for 48 hours. Flow cytometry was used to measure the expression levels of costimulatory molecules (CD80/86) and antigenic peptide recognition complexes (the major histocompatibility complex [MHC] class Ⅰ/Ⅱ) on DCs and T cell activation markers (CD69/28/152) as well as the numbers of CD4⁺ and CD8⁺ T cells. Results ⁶⁰Co γ irradiation significantly increased the apoptosis rate of MLE-12 cells in a dose-dependent manner, and significantly stimulated the expression of CD80/86 and MHC Ⅱ on DCs, without direct activation of T cells. After γ (6 Gy)-irradiated MLE-12 cells were co-cultured with DCs and T lymphocytes for 48 h, there were significant increases in the expression of CD69 and CD28 on T cells, the numbers of CD4⁺ and CD8⁺ T cells, and the expression of CD86 and MHC I on DCs, as compared with the control groups. Conclusion Radiation-injured cells can stimulate antigen presentation by DCs and activate T cells.

Objective To investigate the role of complement in radiation-induced lung injury in mice after chest irradiation with ⁶⁰Co γ-rays at a single dose of 20 Gy. Methods C57BL/6 mice underwent chest irradiation with ⁶⁰Co γ-rays at a single dose of 20 Gy, followed by observation for the inflammatory reaction of the lung tissue in the early stage (within 15 d) and pulmonary fibrosis in the later stage (30 and 180 d). Enzyme-linked immunosorbent assay was used to measure the levels of C2, C3a, C4, and C5b-9 in the lung tissues at 1, 3, 7, 15, 30, and 180 d after irradiation. The expression of complement mRNA in BEAS-2B cells after irradiation was determined using RT-PCR. Results Radiation-induced lung injury in micepresented as inflammatory response in the early stage and fibrosis in the late stage. Complement C2, C4, and C5b-9 complexes were increased in the early period (3 or 7 d) after irradiation (P < 0.05), which might be associated with the inflammatory response induced by irradiation. During 3 to 180 d, complement C3a was significantly higher in the irradiated mice than in the control mice, suggesting a close relationship between C3a and radiation-induced lung injury. The irradiated cells showed increased mRNA expression of C2 and C3, with no changes in the mRNA levels of C4 and C5. Conclusion Different complement proteins have varying responses to radiation-induced lung injury, among which C3a is closely related to radiation-induced lung injury, suggesting that regulating C3a and its receptors may be a new way to prevent and treat radiation-induced lung injury.

OBJECTIVE：To study general chara cteristics and medication of medical damage liability disputes cases caused by medication error ， and to provide references for related departments and medical staff for preventing and reducing medication-induced medical disputes. METHODS ：A total of 240 cases of medical damage liability disputes cases caused by medication error were collected from Peking University ’s Fabao Law Database during Jan. 2001 to Feb. 2020，and analyzed in terms of general situation ，damage outcome ，level of the hospital involved ，liability judgment and compensation ，types of medication error and drug types. RESULTS ：medication-related medical damage liability disputes accounted for 25.3％ of overall medical damage disputes ；the most damage result of patients was death （68.3％）；medical negligence forensic appraisal was conducted as the main appraisal pattern with a proportion of 57.9％；the average case compensation was 203，000 yuan；the hospitals involved were mainly tertiary hospitals （48.8％）；the main type of medication error involved was prescription error ； chemical medicine was mainly involved ，of which the top three categories were systemic antibacterial ，systemic corticosteroids and antipsychotics. CONCLUSIONS ：ADR caused by medication errors are the common causes of medical disputes. Medical institutions should focus on improving the relevant systems and processes ，strengthen the construction of pharmaceutical information and automation system ，and reduce the probability of medication errors ；at the same time ，great importance should be paid to the cultivation of pharmaceutical talents in hospital ，give full play to the role of pharmacists ，and strengthen the monitoring and intervention of medication errors. Finally ，the relevant national judicial departments should constantly improve the settlement mechanism of medical damage liability disputes to provide reasonable protection for both doctors and patients.

Objective:To explore the relationship between insulin resistance, glucose and lipid metabolism related molecules and colorectal polyps.Methods:A total of 262 healthy people who underwent colonoscopy in Shandong cancer hospital from June 2019 to September 2020 were selected. The levels of serum vascular cell adhesion molecule-1 (VCAM-1), fibroblast growth factor 19 (FGF19), insulin like growth factor (IGF-1), fasting blood glucose and fasting blood insulin were detected by enzyme-linked immunosorbent assay (ELISA). Insulin resistance index (HOMA-IR) was calculated, and the influencing factors of occurrence, pathological type, size and number of polyps were analyzed.Results:Among 262 cases, 116 cases were polyp free, 113 cases were adenomatous polyp and 33 cases were inflammatory polyp. HOMA-IR, VCAM-1 and FGF19 in polyp group were 2.904±1.754, (334.415±139.573) ng/ml and (135.865±98.470) pg/ml, respectively, which were higher than 2.369±1.306, (302.480±99.946) ng/ml and(110.694±76.044) ng/ml in non-polyp group, respectively ( P<0.05). Multivariate Logistic regression analysis showed that the gender ( OR=4.269, 95% CI: 1.963-9.405) and FGF19 (77.0-131.4 pg/ml: OR=2.385, 95% CI: 1.155-4.926) were independent factors of colorectal polyps. The gender ( OR=3.799, 95% CI: 1.650-8.748) and FGF19 (77.0-131.4 pg/ml: OR=2.290, 95% CI: 1.072-4.891) were independent factors of colorectal adenomatous polyps. The gender( OR=6.725, 95% CI: 1.853-24.410) and fasting plasma glucose (≥6.5 mmol/L: OR=0.047, 95% CI: 0.009-0.245) were independent factors of colorectal inflammatory polyps. The gender ( OR=3.539, 95% CI: 1.293-9.689) was an independent factor for the occurrence of single polyp. The gender ( OR=5.063, 95% CI: 2.048-12.515), FGF19 (77.0-131.4 pg/ml: OR=2.502, 95% CI: 1.102-5.681), fasting plasma glucose (≥6.5 mmol/L: OR=0.282, 95% CI: 0.095-0.839) were independent factors of multiple polyps. The gender ( OR=3.416, 95% CI: 1.134-10.289) and fasting insulin (≥9.4 μU/ml: OR=9.480, 95% CI: 1.485-60.521) were independent risk factors for colorectal polyps<0.5 cm. The gender ( OR=3.151, 95% CI: 1.244-7.984) and fasting plasma glucose (≥6.5 mmol/L: OR=0.310, 95% CI: 0.102-0.941) were independent risk factors for colorectal polyps with the size of 0.5-0.9 cm. The gender ( OR=22.649, 95% CI: 4.154-123.485), age (55 to 64 years old: OR=4.473, 95% CI: 1.070-18.704; ≥65 years old: OR=5.815, 95% CI: 1.300-26.009), BMI (≥28 kg/m 2: OR=5.310, 95% CI: 1.224-23.032) and FGF19 (77.0-131.4 pg/ml: OR=7.474, 95% CI: 1.903-29.351) were independent factors for colorectal polyps with size ≥ 1.0 cm. Gender stratification analysis showed that FGF19 was an independent factor for the occurrence of male polyps (77.0-131.4 pg/ml: OR=6.109, 95% CI: 1.688-22.104) and adenomas (77.0-131.4 pg/ml: OR=6.401, 95% CI: 1.717-23.864). The age (55 to 64 years old: OR=3.783, 95% CI: 1.052-13.611) and VCAM-1 (≥352.8 ng/ml: OR=4.341, 95% CI: 1.142-16.493) were independent risk factors of female polyps. The age (55 to 64 years old: OR=5.743, 95% CI: 1.205-27.362, ≥65 years old: OR=6.885, 95% CI: 1.143-41.467), VCAM-1 (≥352.8 ng/ml: OR=6.313, 95% CI: 1.415-28.159) and IGF-1 (≥7.6 ng/ml: OR=5.621, 95% CI: 1.069-29.543) were independent factors of female adenoma. Conclusions:The occurrences of colorectal polyps and adenomatous polyps are related to insulin resistance and glucose and lipid metabolism. Serum FGF19 is an independent influencing factor for the occurrence of colorectal polyps and adenomatous polyps, and is a potential serological diagnostic marker and therapeutic target for colorectal polyps and adenomatous polyps.

Objective:To explore the relationship between insulin resistance, glucose and lipid metabolism related molecules and colorectal polyps.Methods:A total of 262 healthy people who underwent colonoscopy in Shandong cancer hospital from June 2019 to September 2020 were selected. The levels of serum vascular cell adhesion molecule-1 (VCAM-1), fibroblast growth factor 19 (FGF19), insulin like growth factor (IGF-1), fasting blood glucose and fasting blood insulin were detected by enzyme-linked immunosorbent assay (ELISA). Insulin resistance index (HOMA-IR) was calculated, and the influencing factors of occurrence, pathological type, size and number of polyps were analyzed.Results:Among 262 cases, 116 cases were polyp free, 113 cases were adenomatous polyp and 33 cases were inflammatory polyp. HOMA-IR, VCAM-1 and FGF19 in polyp group were 2.904±1.754, (334.415±139.573) ng/ml and (135.865±98.470) pg/ml, respectively, which were higher than 2.369±1.306, (302.480±99.946) ng/ml and(110.694±76.044) ng/ml in non-polyp group, respectively ( P<0.05). Multivariate Logistic regression analysis showed that the gender ( OR=4.269, 95% CI: 1.963-9.405) and FGF19 (77.0-131.4 pg/ml: OR=2.385, 95% CI: 1.155-4.926) were independent factors of colorectal polyps. The gender ( OR=3.799, 95% CI: 1.650-8.748) and FGF19 (77.0-131.4 pg/ml: OR=2.290, 95% CI: 1.072-4.891) were independent factors of colorectal adenomatous polyps. The gender( OR=6.725, 95% CI: 1.853-24.410) and fasting plasma glucose (≥6.5 mmol/L: OR=0.047, 95% CI: 0.009-0.245) were independent factors of colorectal inflammatory polyps. The gender ( OR=3.539, 95% CI: 1.293-9.689) was an independent factor for the occurrence of single polyp. The gender ( OR=5.063, 95% CI: 2.048-12.515), FGF19 (77.0-131.4 pg/ml: OR=2.502, 95% CI: 1.102-5.681), fasting plasma glucose (≥6.5 mmol/L: OR=0.282, 95% CI: 0.095-0.839) were independent factors of multiple polyps. The gender ( OR=3.416, 95% CI: 1.134-10.289) and fasting insulin (≥9.4 μU/ml: OR=9.480, 95% CI: 1.485-60.521) were independent risk factors for colorectal polyps<0.5 cm. The gender ( OR=3.151, 95% CI: 1.244-7.984) and fasting plasma glucose (≥6.5 mmol/L: OR=0.310, 95% CI: 0.102-0.941) were independent risk factors for colorectal polyps with the size of 0.5-0.9 cm. The gender ( OR=22.649, 95% CI: 4.154-123.485), age (55 to 64 years old: OR=4.473, 95% CI: 1.070-18.704; ≥65 years old: OR=5.815, 95% CI: 1.300-26.009), BMI (≥28 kg/m 2: OR=5.310, 95% CI: 1.224-23.032) and FGF19 (77.0-131.4 pg/ml: OR=7.474, 95% CI: 1.903-29.351) were independent factors for colorectal polyps with size ≥ 1.0 cm. Gender stratification analysis showed that FGF19 was an independent factor for the occurrence of male polyps (77.0-131.4 pg/ml: OR=6.109, 95% CI: 1.688-22.104) and adenomas (77.0-131.4 pg/ml: OR=6.401, 95% CI: 1.717-23.864). The age (55 to 64 years old: OR=3.783, 95% CI: 1.052-13.611) and VCAM-1 (≥352.8 ng/ml: OR=4.341, 95% CI: 1.142-16.493) were independent risk factors of female polyps. The age (55 to 64 years old: OR=5.743, 95% CI: 1.205-27.362, ≥65 years old: OR=6.885, 95% CI: 1.143-41.467), VCAM-1 (≥352.8 ng/ml: OR=6.313, 95% CI: 1.415-28.159) and IGF-1 (≥7.6 ng/ml: OR=5.621, 95% CI: 1.069-29.543) were independent factors of female adenoma. Conclusions:The occurrences of colorectal polyps and adenomatous polyps are related to insulin resistance and glucose and lipid metabolism. Serum FGF19 is an independent influencing factor for the occurrence of colorectal polyps and adenomatous polyps, and is a potential serological diagnostic marker and therapeutic target for colorectal polyps and adenomatous polyps.

OBJECTIVE：To evaluate guidelines f or health technology assessment （HTA）at home and abroad ，and to provide reference for scientific formulation of HTA guidelines in China. METHODS ：Databases including PubMed ，Embase，Guidenlines International Network and 83 official websites from 26 countries governments and academic organizations were searched to collect HTA guidelines from inception to April 2020. Two reviewers independently screened literature and extracted data ，including basic characteristics， content of guideline and assessment content. Then a descriptive analysis was conducted. RESULTS & CONCLUSIONS：A total of 19 guidelines published during 2001 to 2018 were included ，7 guidelines（36.8％）were published in 2015-2020；in addition to 1 guideline from WHO ，14 guidelines （73.7％）were published in Europeand ，2 guidelines（10.5％） in North America and 1 guideline each from South America and Asia （5.3％）. There were 11 guidelines（57.9％）developed by academic organizations and 8 guidelines（42.1％）by health administration ；11 guidelines（57.9％）were evidence-based ，while the others weren ’t evidence- based （42.1％）. The purpose ，content and object of assessment are demonstrated in 19 guidelines；18 guidelines specified the assessment method （94.7％），and 16 guidelines（84.2％）defined the subject of assessment ；14 guidelines （73.7％）specified the HTA assessment process ；12 guidelines（63.3％）mentioned the conflict of interest in HTA assessment process；7 guidelines（36.8％）mentioned the application of assessment results. There are some differences in the formulation methods and contents of HTA guidelines in foreign countries ，but the core contents ar e basically the same. At present ，there is a lack of HTA guidelines in China. We can refer to foreign guidelines，and establish applicable HTA guidelines which aresuitable for national conditions ，so as to provide scientific guidance for HTA research.

When wars, major disasters, or epidemics of the infectious diseases occur, existing medical facilities are usually unable to implement timely and effective treatment for patients, or the reception capacity is difficult to meet the surge in demand for health care. The makeshift emergency hospitals are built for patient reception, treatment and even isolation for infectious disease control. The makeshift hospitals have developed and improved in modern times, including mobile field hospitals, field tent hospitals and navy hospital ships equipped with advanced equipment and commonly used for military purposes, or temporary hospitals built in large public buildings and newly built hospitals in support of disaster relief and humanitarian operation. Makeshift hospitals have played an important role in response to many disasters and epidemics globally. This paper briefly summarizes the history, types, and applications of makeshift hospitals in disasters and epidemic responses.