Ethical review represents the core of the scientific and technological ethical governance， and its quality depends on the participation of ethics. The absence of ethics and ethical experts will compromise the quality of the review. According to the spirit of the Guidelines on Strengthening the Governance over Ethics in Science and Technology， this paper analyzed the process of separating scientific and technological ethics from the field of scientific research morality， clarified the ethical attributes of ethical review， and argued that scientific research and technological innovation activities originated from ethics. On this basis， the fundamental principle of “ethics first” was proposed， aiming to proactively embed ethical considerations throughout the entire process of scientific and technological activities. This principle was the primary requirement for ensuring governance effectiveness and can also eliminate the risk of ethics being obscured in ethical governance. In practice， “ethics first” manifested specifically in dimensions such as prioritizing academic systems， prioritizing publicity， education， and training， as well as further advancing ethical considerations.

“Integrated elderly care and medical services” is a new model of elderly care that relies on medical care as a guarantee， rehabilitation as a support， and combines ongoing medical treatment with nurturing， offering comprehensive therapy. This new type of elderly care model also poses new job requirements for elderly care workers. However， there is currently a large shortage of elderly care workers， along with prevalent issues such as low professional quality， low education level， and an older average age. The main reasons for this situation are low welfare benefits， low social status， and an incomplete promotion system in the industry， resulting in low social recognition of the industry， a shortage of employees， and a high number of resignations. Based on this， it is suggested to expand the number of the elderly care team and enhance the quality of the elderly care team by improving the career development system， increasing salary and welfare benefits， and expanding social recognition.

Objective To investigate whether orexin A(orexin-A),orexin receptor 1(OX1R)and orexin receptor 2(OX2R)are involved in iron death and lipid peroxidation regulation in chronically unpredictable mild stress(CUMS)depressed rats.Methods Forty rats were randomly divided into a normal group(NC group),a modeling group(Mod group),an exogenous Orexin-A group(Orexin-A group,),and an OX1R/OX2R blocker group(TCS1102 group),with 10 rats in each group.After modeling,behavioral changes were observed using the absent field test(OFT),sugar-water preference test(SPT)and forced swimming test(FST),action potential(PA)and resting membrane potential(Vm)were detected by diaphragm-clamp technique,Orexin-A/OX1R/OX2R protein expression in orbital frontal cortex(OFC)tissues was detected by protein immunoblotting(WB)method,RT-PCR The mRNA expression of glutathione peroxidase 4(GPX4),long chain acyl coenzyme A synthase 4(ACSL4)and cysteine/glutamate transporter light chain(SLC7A11)were detected by RT-PCR method,and the intensity of the expression of rat glial fibrillary acidic protein(GFAP)and lipid peroxidation product 4-hydroxynon-enal(4-HNE)was labeled by immunofluorescence.Results Compared with the NC group,there were significant differences in OFT,SPT and FST behavioral in the Mod group(P<0.01),with lower number of PA issuance(P<0.001),higher Vm(P<0.01),and higher expression of Orexin-A/OX1R/OX2R proteins(P<0.01,P<0.001,and P<0.001).GPX4/SLC7A11 mRNA expression was decreased(P<0.01),ACSL4 mRNA expression was elevated(P<0.01),and the fluorescence intensity expression of both GFAP and 4-HNE was elevated(P<0.001);the number of PA issuance was decreased in the Orexin-A group compared to the Mod group(P<0.05),and the Orexin-A/OX1R/OX2R protein expression was elevated(P<0.05,P<0.01),GPX4/SLC7A11 mRNA ex-pression was decreased(P<0.05),ACSL4 mRNA expression was elevated(P<0.05),and the fluorescence in-tensity of GFAP and 4-HNE expression was elevated(P<0.05,P<0.01);the TCS1102 group had higher expres-sion of GFAP and 4-HNE in the behavioral,Orexin-A/OX1R/OX2R protein expression,PA and Vm,GPX4/SLC7A11/ACSL4 mRNA,and GFAP and 4-HNE fluorescence intensity expression showed a reversed trend.Con-clusions Orexin-A/OX1R/OX2R is involved in the regulation of iron death and lipid peroxidation in CUMS de-pressed rats,and the mechanism may be that Orexin-A enhances the excitability of OFC neurons by activating the OX1R/OX2R signaling pathway,up-regulates the expression of the key factor of iron death,ACSL4/4-HNE,and decreases the expression of GPX4/SLC7A11,which promotes lipid peroxidation and iron death.

Objective To investigate whether orexin A(orexin-A),orexin receptor 1(OX1R)and orexin receptor 2(OX2R)are involved in iron death and lipid peroxidation regulation in chronically unpredictable mild stress(CUMS)depressed rats.Methods Forty rats were randomly divided into a normal group(NC group),a modeling group(Mod group),an exogenous Orexin-A group(Orexin-A group,),and an OX1R/OX2R blocker group(TCS1102 group),with 10 rats in each group.After modeling,behavioral changes were observed using the absent field test(OFT),sugar-water preference test(SPT)and forced swimming test(FST),action potential(PA)and resting membrane potential(Vm)were detected by diaphragm-clamp technique,Orexin-A/OX1R/OX2R protein expression in orbital frontal cortex(OFC)tissues was detected by protein immunoblotting(WB)method,RT-PCR The mRNA expression of glutathione peroxidase 4(GPX4),long chain acyl coenzyme A synthase 4(ACSL4)and cysteine/glutamate transporter light chain(SLC7A11)were detected by RT-PCR method,and the intensity of the expression of rat glial fibrillary acidic protein(GFAP)and lipid peroxidation product 4-hydroxynon-enal(4-HNE)was labeled by immunofluorescence.Results Compared with the NC group,there were significant differences in OFT,SPT and FST behavioral in the Mod group(P<0.01),with lower number of PA issuance(P<0.001),higher Vm(P<0.01),and higher expression of Orexin-A/OX1R/OX2R proteins(P<0.01,P<0.001,and P<0.001).GPX4/SLC7A11 mRNA expression was decreased(P<0.01),ACSL4 mRNA expression was elevated(P<0.01),and the fluorescence intensity expression of both GFAP and 4-HNE was elevated(P<0.001);the number of PA issuance was decreased in the Orexin-A group compared to the Mod group(P<0.05),and the Orexin-A/OX1R/OX2R protein expression was elevated(P<0.05,P<0.01),GPX4/SLC7A11 mRNA ex-pression was decreased(P<0.05),ACSL4 mRNA expression was elevated(P<0.05),and the fluorescence in-tensity of GFAP and 4-HNE expression was elevated(P<0.05,P<0.01);the TCS1102 group had higher expres-sion of GFAP and 4-HNE in the behavioral,Orexin-A/OX1R/OX2R protein expression,PA and Vm,GPX4/SLC7A11/ACSL4 mRNA,and GFAP and 4-HNE fluorescence intensity expression showed a reversed trend.Con-clusions Orexin-A/OX1R/OX2R is involved in the regulation of iron death and lipid peroxidation in CUMS de-pressed rats,and the mechanism may be that Orexin-A enhances the excitability of OFC neurons by activating the OX1R/OX2R signaling pathway,up-regulates the expression of the key factor of iron death,ACSL4/4-HNE,and decreases the expression of GPX4/SLC7A11,which promotes lipid peroxidation and iron death.

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.

Background::Gut-resident macrophages (gMacs) supplemented by monocytes-to-gMacs differentiation play a critical role in maintaining intestinal homeostasis. Activating transcription factor 4 (ATF4) is involved in immune cell differentiation. We therefore set out to investigate the role of ATF4-regulated monocytes-to-gMacs differentiation in sepsis-induced intestinal injury.Methods::Sepsis was induced in C57BL/6 wild type (WT) mice and Atf4-knockdown ( Atf4+/-) mice by cecal ligation and puncture or administration of lipopolysaccharide (LPS). Colon, peripheral blood mononuclear cells, sera, lung, liver, and mesenteric lymph nodes were collected for flow cytometry, hematoxylin and eosin staining, immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. Results::CD64, CD11b, Ly6C, major histocompatibility complex-II (MHC-II), CX3CR1, Ly6G, and SSC were identified as optimal primary markers for detecting the process of monocytes-to-gMacs differentiation in the colon of WT mice. Monocytes-to-gMacs differentiation was impaired in the colon during sepsis and was associated with decreased expression of ATF4 in P1 (Ly6C hi monocytes), the precursor cells of gMacs. Atf4 knockdown exacerbated the impairment of monocytes-to-gMacs differentiation in response to LPS, resulting in a significant reduction of gMacs in the colon. Furthermore, compared with WT mice, Atf4+/- mice exhibited higher pathology scores, increased expression of inflammatory factor genes ( TNF-α, IL-1β), suppressed expression of CD31 and vascular endothelial-cadherin in the colon, and increased translocation of intestinal bacteria to lymph nodes and lungs following exposure to LPS. However, the aggravation of sepsis-induced intestinal injury resulting from Atf4 knockdown was not caused by the enhanced inflammatory effect of Ly6C hi monocytes and gMacs. Conclusion::ATF4, as a novel regulator of monocytes-to-gMacs differentiation, plays a critical role in protecting mice against sepsis-induced intestinal injury, suggesting that ATF4 might be a potential therapeutic target for sepsis treatment.

BACKGROUND: Advances in organoid culture technology have provided a greater understanding of disease pathogenesis, which has been rarely studied in sepsis before. We aim to establish a suitable organoids-based intestinal injury model for sepsis. METHODS: Stable passaged organoids were constructed and pre-treated with lipopolysaccharide (LPS) to mimic sepsis-induced intestinal injury. The LPS-induced sepsis model was used as a reference. We used quantitative real-time polymerase chain reaction to evaluate the RNA levels of inflammatory factors and antimicrobial peptides. Enzyme-linked immunosorbent assay was used to evaluate the protein levels, hematoxylin and eosin staining was used to evaluate the pathology of the small intestine of mice, and immunohistochemistry and immunofluorescence were used to evaluate the intestinal epithelial barrier function. Perkin Elmer Operetta™ was used to obtain high-resolution images of three-dimensional organoids. RESULTS: An LPS concentration >150 μg/mL after 24 h was identified to cause organoid growth restriction. The fluorescence intensity of zonula occludens-1 and occludins at LPS concentrations >100 μg/mL decreased significantly after 24 h. After LPS stimulation for 8 h, the RNA expression levels of interleukin (IL)-1α, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, IL-6, and regenerating islet-derived protein 3 alpha, beta, and gamma increased. These results resembled those of intestinal epithelial layer alterations in a mouse sepsis model. For IL-10, the RNA expression level increased only when the LPS level >200 μg/mL for 24 h. CONCLUSIONS This study provides the primary intestinal in vitro model to study the effects of LPS-induced intestinal injury resembling sepsis. This model provides a platform for immune associated mechanism exploration and effective drug screening.
Mice ; Animals ; Lipopolysaccharides/toxicity* ; Sepsis ; Intestinal Diseases ; Tumor Necrosis Factor-alpha ; Disease Models, Animal ; Organoids ; RNA

ObjectiveTo develop and validate a predictive model to individually predict the risk of patients with stroke in the eICU Collaborative Research Database for early clinical identification and intervention. MethodIndividual patient data （200 859 cases） from a national multicenter cohort study （eICU database） were selected， and the patients with stroke in neurological diseases （9 037 cases） were selected for statistical analysis. The main outcome was hospital mortality. The Glasgow Coma scale （GCS） was used to divide all patients with stroke into stroke in meridian and stroke in viscera （GCS≤14 for stroke in viscera and GCS=15 for stroke in meridian）. The patients were then divided into a training set and a test set according to 7∶3， respectively， to evaluate the differences in hospital mortality between the two groups. The multivariate logistic regression was used to analyze the related factors affecting the prognosis of the two groups， and a predictive model was established. Receiver operator characteristic （ROC） curves were used to assess the discrimination of the predictive model. ResultThe predictive model based on 9 037 patients with stroke was established. The predictors of the stroke in meridian （4 475 cases） included pulmonary infection， mechanical ventilation， acute physiology， and chronic health status scoring system Ⅳ （APACHE Ⅳ） score. The predictors of the stroke in viscera （4 562 cases） included anticoagulation therapy （AT）， mechanical ventilation， acute physiology， and APACHE Ⅳ score. According to the predictors， the predictive models of the stroke in meridian and the stroke in viscera were constructed， respectively. The areas under the curve （AUC） of ROC of the training set and the test set of the predictive models of the stroke in meridian were 0.845 ［95% confidence interval （CI） （0.811， 0.879）］ and 0.807 ［95% CI （0.751， 0.863）］， respectively. The areas under the ROC curve of the training set and test set of the predictive models of the stroke in viscera were 0.799 ［95% CI （0.781， 0.817）］ and 0.805 ［95% CI （0.778， 0.832）］， respectively. The AUC of the predictive model of the training set and the test set were both above 0.7. ConclusionThe model established in this study can conveniently， directly， and accurately predict the hospital mortality risk of patients with stroke. Physicians and other healthcare professionals can use this predictive approach to provide early care planning and clinical interventions for patients with stroke during their hospital stay.

Objective: To investigate the clinical research of Guo's Liulian therapy in treating acute pancreatitis intestinal mucosal barrier dysfunction and provide reference for the patients with acute pancreatitis. Methods: The 68 patients with acute pancreatitis who were admitted to our hospital from September 2016 to May 2018 were selected as study subjects. According to the random number table method, the patients were divided into the observation group and the control group, with 34 cases in each group. The patients in the control group were treated with conventional western medicine. The patients in the observation group were treated with Guo's Liulian therapy on the basis of the above treatment. The time of intestinal paralysis was compared between the two groups. The changes of intestinal mucosal barrier function and serum inflammatory factor related indexes before and after treatment were analyzed in the two groups. The difference of therapeutic effects between the two groups was observed. Results: In the observation group, the abdominal pain relief time, abdominal distention relief time, bowel sound recovery time, and first bowel anus defecation time were significantly lower than those in the control group (t=7.621, 5.332 6.625, 8.762, all Ps<0.01). After treatment, serum LPS, DAO, ET, D-lactic acid, TNF-α, IL-1, IL-6, IL-8, and IL-10 and urine L/M were significantly lower in the observation group, while the serum ITF and MFG-E8 were significantly higher in the observation group (t=9.856, 6.974, 9.784, 16.068, 9.550, 12.506, 22.343, 16.625, 6.774, 23.469, 20.118, 23.031, all Ps<0.01). Conclusions The Guo's Liulian therapy treatment of acute pancreatitis in patients with intestinal mucosal barrier dysfunction can reduce the palsy remission time, reduce inflammation, increase serum ITF, MFG-E8 levels, repair of intestinal permeability, and improve the intestinal barrier function.

Objective To investigate the clinical efficacy of laparoscopic anatomical left hepatectomy by guided middle hepatic vein approach.Methods The clinical data of 21 patients undergone anatomical left hepatectomy from Oct.2015 to Jul.2018 were retrospectively analyzed.Results Among the 21 cases,the primary hepatocellular carcinoma were found in 4 patients (19.1％),the cholangiocarcinoma in 1 patients (4.8％),the giant hepatic hemangioma in 1 patients (4.8％),the hepatolithiasis in 15 patients (71.3％).All 21 patients were operated under laparoscopy and recovered.The operative time was 160-380 min,the average operative time was(248 ± 56)min,the intraoperative blood loss was 100-700 ml.The average blood loss was (250 ± 40)ml,the average length of hospital stay of the patients was 8-14 (10 ± 2)d.Conclusions Laparoscopic anatomical left hepatectomy guided by middle hepatic vein approach is a safe and effective operation.