Mevalonate metabolism plays an important role in regulating tumor growth and progression; however, its role in immune evasion and immune checkpoint modulation remains unclear. Here, we found that non-small cell lung cancer (NSCLC) patients with higher plasma mevalonate response better to anti-PD-(L)1 therapy, as indicated by prolonged progression-free survival and overall survival. Plasma mevalonate levels were positively correlated with programmed death ligand-1 (PD-L1) expression in tumor tissues. In NSCLC cell lines and patient-derived cells, supplementation of mevalonate significantly up-regulated the expression of PD-L1, whereas deprivation of mevalonate reduced PD-L1 expression. Mevalonate increased CD274 mRNA level but did not affect CD274 transcription. Further, we confirmed that mevalonate improved CD274 mRNA stability. Mevalonate promoted the affinity of the AU-rich element-binding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA. By in vivo study, we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1, increased the infiltration of CD8⁺ T cells, and improved cytotoxic function of T cells. Collectively, our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody, and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.

[This corrects the article DOI: 10.1016/j.apsb.2023.04.002.].

OBJECTIVES: To study the effect of glucose metabolism disorders on the short-term prognosis in neonates with asphyxia. METHODS: A retrospective analysis was performed on the medical data of the neonates with asphyxia who were admitted to 52 hospitals in Hubei Province of China from January to December, 2018 and had blood glucose data within 12 hours after birth. Their blood glucose data at 1, 2, 6, and 12 hours after birth (with an allowable time error of 0.5 hour) were recorded. According to the presence or absence of brain injury and/or death during hospitalization, the neonates were divided into a poor prognosis group with 693 neonates and a good prognosis group with 779 neonates. The two groups were compared in the incidence of glucose metabolism disorders within 12 hours after birth and short-term prognosis. RESULTS: Compared with the good prognosis group, the poor prognosis group had a significantly higher proportion of neonates from secondary hospitals (48.5% vs 42.6%, CONCLUSIONS Recurrent hyperglycemia in neonates with asphyxia may suggest poor short-term prognosis, and it is necessary to strengthen the early monitoring and management of the nervous system in such neonates.
Asphyxia ; Asphyxia Neonatorum/epidemiology* ; Humans ; Hyperglycemia ; Infant, Newborn ; Prognosis ; Retrospective Studies

Objective To study the preventive effect of microinsulin on cognitive dysfunction induced by sevoflurane inhalation anesthesia in rats and its possible mechanism. Methods Sixty newborn rats were randomly divided into control group (CON), insulin prevention low dose group (LIP), insulin prevention hihg dose group (HIP), and sevoflurane model group (MOD). The prevention group and the model group were induced by sevoflurane to construct rat cognitive dysfunction model. Morris water maze directional sailing test and space exploration test were used to evaluate the learning and memory function of rats; HE staining was used to observe the pathological morphological changes of hippocampus in rats; Flow cytometry was used to detect the hippocampus of rats cell apoptosis; Detection of rapamycin target protein (mTOR) and eukaryotic peptide chain elongation factor 2 (eEF-2) mRNA levels in hippocampus by RT-PCR; The expression levels of brain-derived neurotrophic factor (BDNF), post-synaptic dense protein-95 (PSD-95), synapsin- I, and calmodulin kinase II α (CaMK II α), mTOR and eEF-2 protein were detected by Western blotting. Results The result of the Morris water maze experiment showed that insulin significantly reduced the escape latency and swimming distance of rats, and increased the number of crossing platforms; Flow cytometry result showed that the insulin prevention group significantly inhibited the apoptosis of rat brain neurons, and the inhibition effect of high-dose insulin prevention group was more obvious; RT-PCR and Western blotting analysis found that the expression levels of mTOR and eEF-2 mRNA and proteins in the hippocampus of the model group increased significantly, while the expression levels of BDNF, PSD-95, synapsin- I, and CaMK II α proteins reduced significantly. The expression levels of mTOR and eEF-2 mRNA and proteins in the hippocampus of rats in the insulin prevention group decreased significantly, while the expression levels of BDNF, PSD-95, synapsin- I, and CaMK II α protein increased significantly. The difference was statistically significant (P < 0.05). Conclusion Trace insulin can increase the expression of synapse-related proteins in the hippocampus of cognitive dysfunction rats, reduce their mTOR and eEF-2 mRNA expression levels, and prevent sevoflurane-induced cognitive impairment in rats. The mechanism may be related to the regulation of mTOR-eEF-2 approach.

To address the increasing need for detecting and validating protein biomarkers in clinical specimens, mass spectrometry (MS)-based targeted proteomic techniques, including the selected reaction monitoring (SRM), parallel reaction monitoring (PRM), and massively parallel data-independent acquisition (DIA), have been developed. For optimal performance, they require the fragment ion spectra of targeted peptides as prior knowledge. In this report, we describe a MS pipe-line and spectral resource to support targeted proteomics studies for human tissue samples. To build the spectral resource, we integrated common open-source MS computational tools to assemble a freely accessible computational workflow based on Docker. We then applied the workflow to gen-erate DPHL, a comprehensive DIA pan-human library, from 1096 data-dependent acquisition (DDA) MS raw files for 16 types of cancer samples. This extensive spectral resource was then applied to a proteomic study of 17 prostate cancer (PCa) patients. Thereafter, PRM validation was applied to a larger study of 57 PCa patients and the differential expression of three proteins in prostate tumor was validated. As a second application, the DPHL spectral resource was applied to a study consisting of plasma samples from 19 diffuse large B cell lymphoma (DLBCL) patients and 18 healthy control subjects. Differentially expressed proteins between DLBCL patients and healthy control subjects were detected by DIA-MS and confirmed by PRM. These data demonstrate that the DPHL supports DIA and PRM MS pipelines for robust protein biomarker discovery. DPHL is freely accessible at https://www.iprox.org/page/project.html?id=IPX0001400000.

Objective To investigate the clinical features of patients with acute ST-segment elevation myocardial infarction (STEMI) comorbid with diabetes mellitus (DM) and to analyze the prognosis within 12 months after primary percutaneous coronary intervention (pre-PCI). Methods A total of 375 STEMI patients were divided into the diabetes group (n=140) and the normal blood glucose group(n=235) according to whether they met the diagnostic criteria of DH. The clinical data,characteristics of coronary artery lesions,type of stent implant,rate of coronary slow flow or no-reflow after pre-PCI, and the prognosis within 12 months after PCI of the two groups were investigated.Results Patient in the diabetes group presented with higher mean age ,higher comorbid rates of hypertension , hyperlipidemia and heart function of Killip class Ш and above than patients in the normal blood glucose group (all P<0.05). patients in the diabetes group had higher rates of slow reflow /no-reflow after PCI(12.9% vs.5.5%,P=0.013),higher percentages of 3-ressel disease(40.7% vs. 28.9%,P=0.019)and lef t main lesions(13.6% vs. 7.2%,P=0.044). The in-hospital mortality rates(6.4% vs.1.7%,P=0.020),revascularization rates within 12 months(7.9% vs.0.9%,P=0.001)and incidence of heart failure(7.9% vs. 2.6%,P=0.017)were all higher in the diabetes group. Conclusions STEMI patients comorbid with DM were relatively older, had higher comorbidities of hypertension,hyperlipidemia, three-vessel disease, left main coronary lesions and higher mortality during hospitalization. No significant increase in cardiac death and recurrent myocardial infarction were deserved during the follow-up period. These patients may benefit more from early intervention.

Objective To investigate the curative effect and safety of human umbilical cord mesenchymal stem cells(UCMSCs)on the treatment of refractory acute graft versus host disease(aGVHD)of children after allogeneic hematopoietic stem cell transplantation.Methods Five children with refructory aGVHD who hospitalized at the De-partment of Pediatrics,the Navy General Hospital were treated with UCMSCs retrospectively.Among them,1 case was male and 4 cases were female,who aged from 18 months old to 15 years old.Two cases had aplastic anemia(AA),1 case with acute myeloblastic leukemia(AML-M2-CR2),1 case with acute lymphoblastic leukemia(ALL-CR1)and 1 case with myelodysplastic syndrome(MDS). Three cases received peripheral blood stem cell transplantation from HLA-matched sibling donor,1 case received mother′s peripheral blood and bone marrow stem cell transplantation from the haploid donor,and 1 case received father′s peripheral blood and bone marrow stem cell transplantation from the haploid donor(both 3/6 HLA locus matched).Prophylaxis for graft versus host disease(GVHD)was performed by using ciclosporin A and methotrexate in 1 case,others used anti-thymocyte globulin,ciclosporin A,mycophenolate mofetil and methotrexate for GVHD prophylaxis. All children developed refractory aGVHD,and they received 3-5 kinds of immunosuppressive agents to treat the refractory aGVHD,but the therapeutic effect was very poor.Then the children received UCMSCs infusion 2 or 3 times(once a week),the UCMSCs dose given was(1.5-2.0)×106per kg body weight,the curative effect and adverse reactions were apparent after infusion.Results All the children with re-fractory aGVHD were improved after treatment,the overall response was 100%,and 2 cases were healed and dis-charged,1 case suffered from relapsed of aGVHD and died,and the other 2 cases suffered from relapsed of aGVHD and died of thrombotic microvascular disease.On adverse reaction was monitored during infusion,and 2 cases had disease-free survival during 2 years follow-up,without tumour and primary disease recurrence.Conclusions UCMSCs is safe and effective for treatment of refractory aGVHD.In order to improve the curative effect and disease-free survival,the UCMSCs should be reduced early,which can reduce the application and side effects of the immunosuppressor.

It is uncommon for tire explosion related injuries on the lower extremity. The bilateral lower extremities were injured by tire explosion when the patient was seated in a bus. She sustained an open fracture with partial bone loss in the right calcaneus (a comminuted fracture in the right ankle joint) and a closed comminuted fracture in the left tibia and fibula. This damage was caused by uncontacted tire explosion, thanks to a thick floor between the exploded tire and the patient's feet. This type of injury on lower extremity caused by uncontacted tire explosion was uncommon.

This study is prepared to provide the basis of rheological parameters for the additional quality standard of ophthalmic gels, the rheological properties of the ophthalmic gels and the other three types of ophthalmic preparations. The medicines were compared through the study of the rheological properties for four types of ophthalmic preparations. The cone-plate rheometer was used to determine the dynamic and steady rheological parameters of four types of ophthalmic preparations. The similarities and differences of the measured results were analyzed to summarize the rheological indexes and parameters which are applied to distinguish the ophthalmic gels and the other types of ophthalmic preparations. ① The elastic modulus should be greater than the viscous modulus for the ophthalmic gels in the range of the linear viscoelastic region. ② The ophthalmic gels should be shear thinning non-Newtonian fluid with a certain yield stress and thixotropy. ③ The dynamic viscosity of the ophthalmic gels should be greater than 0.5 Pa·S at the temperature of 25℃ with the 50 s^-1 shear rate. The typical rheological indexes and parameters of the ophthalmic gels were proposed in this article. The determination methods are simple and feasible. The rheological indexes and parameters have an important significance in the prescription design, production technology and quality control of the ophthalmic gels.

Objective:To evaluate the clinical efficacy of tendon-regulating manipulation plus kinesiotherapy in treating low back pain. Methods:Sixty patients were randomized into a treatment group and a control group by using the random number table, 30 cases in each group. The treatment group was intervened by tendon-regulating manipulation plus kinesiotherapy, while the control group was by the tendon-regulating manipulation alone. The lumbar lordosis was measured by X-ray (side view), the pain was evaluated by analgesy meter, the lumbar range of motion was by using goniometer, and the function was judged by Oswestry disability index (ODI) before and after treatment, and the therapeutic efficacy was also observed. Results:After treatment, the pain level was significantly reduced, lumbar lordosis was significantly increased, the lumbar range of motion was markedly improved, and the ODI score significantly dropped (allP<0.05) in both groups; the improvement of each item in the treatment group was more significant than that in the control group (allP<0.05). The total effective rate was 90.0% in the treatment group versus 63.3% in the control group, and the difference was statistically significant (P<0.05). Conclusion:In the treatment of low back pain, tendon-regulating manipulation plus kinesiotherapy can mitigate topical pain, improve the motion of low back, enhance the quality of life, and produce a more significant therapeutic efficacy compared to tendon-regulating manipulation alone.