Objective:To explore the role of NK cells in allogeneic hematopoietic stem cell micro-transplantation(MST)in the treatment of patients with acute myeloid leukemia(AML).Methods:Data from 93 AML patients treated with MST at our center from 2013-2018 were retrospectively analyzed.The induction regimen was anthracycline and cytarabine combined with peripheral blood stem cells transplantation mobilization by granulocyte colony stimulating factor(GPBSC),followed by 2-4 courses of intensive treatment with medium to high doses of cytarabine combined with GPBSC after achieving complete remission(CR).The therapeutic effects of one and two courses of MST induction therapy on 42 patients who did not reach CR before transplantation were evaluated.Cox proportional hazards regression analysis was used to analyze the impact of donor NK cell dose and KIR genotype,including KIR ligand mismatch,2DS1,haplotype,and HLA-Cw ligands on survival prognosis of patients.Results:Forty-two patients received MST induction therapy,and the CR rate was 57.1％after 1 course and 73.7％after 2 courses.Multivariate analysis showed that,medium and high doses of NK cells was significantly associated with improved disease-free survival(DFS)of patients(HR=0.27,P=0.005;HR=0.21,P=0.001),and high doses of NK cells was significantly associated with improved overall survival(OS)of patients(HR=0.15,P=0.000).Donor 2DS1 positive significantly increases OS of patients(HR=0.25,P=0.011).For high-risk patients under 60 years old,patients of the donor-recipient KIR ligand mismatch group had longer DFS compared to the nonmismatch group(P=0.036);donor 2DS1 positive significantly prolonged OS of patients(P=0.009).Conclusion:NK cell dose,KIR ligand mismatch and 2DS1 influence the therapeutic effect of MST,improve the survival of AML patients.

Phosphatase and tensin-homolog deleted on chromosome 10 (PTEN) is an important cancer suppressor gene. Its pathogenic mutation leads to PTEN hamartoma tumor syndrome (PHTS), a rare syndrome also known as Cowden syndrome, which is relevant to early-onset hereditary breast cancer (BC). In this paper, we report three patients with unilateral multicentric BC and synchronous and metachronous bilateral BC who harbored PTEN gene mutations, and summarize the clinical manifestations, pathological characteristics, diagnosis, treatment and follow-up outcomes to provide reference for management of PTEN gene mutation-related BC among the Cowden syndrome population.

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis

This study engineered β-carotene ketolase CrtW and β-carotene hydroxylase CrtZ to improve biosynthesis of astaxanthin in Escherichia coli. Firstly, crtW was randomly mutated to increase CrtW activities on conversion from β-carotene to astaxanthin. A crtW* mutant with A6T, T105A and L239M mutations has improved 5.35-fold astaxanthin production compared with the wild-type control. Secondly, the expression levels of crtW* and crtZ on chromosomal were balanced by simultaneous modulation RBS regions of their genes using RBS library. The strain RBS54 selected from RBS library, directed the pathway exclusively towards the desired product astaxanthin as predominant carotenoid (99%). Lastly, the number of chromosomal copies of the balanced crtW-crtZ cassette from RBS54 was increased using a Cre-loxP based technique, and a strain with 30 copies of the crtW*-crtZ cassette was selected. This final strain DL-A008 had a 9.8-fold increase of astaxanthin production compared with the wild-type control. Fed-batch fermentation showed that DL-A008 produced astaxanthin as predominant carotenoid (99%) with a specific titer of 0.88 g·L without addition of inducer. In conclusion, through constructing crtW mutation, balancing the expression levels between crtW* and crtZ, and increasing the copy number of the balanced crtW*-crtZ cassette, the activities of β-carotene ketolase and β-carotene hydroxylase were improved for conversion of β-carotene to astaxanthin with higher efficiency. The series of conventional and novel metabolic engineering strategies were designed and applied to construct the astaxanthin hetero-producer strain of E. coli, possibly offering a general approach for the construction of stable hetero-producer strains for other natural products.

Objective: To investigate the current status of antithrombotic strategy for elderly patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) after stent implantation in Beijing area and to study the safety and efficacy of different therapeutic strategy. Methods: A total of 467 relevant patients were enrolled by re-travelling electronic medical records from 12 hospitals in Beijing area. The patients' mean age was (78.70±3.32) years and they were divided into 2 groups by antithrombotic therapy condition: Triple therapy group, n=17 (3.64％), Double therapy group, n=450 (96.36％). The incidence of major adverse cardiac and cerebral events (MACCE) including all-caused death, non-fatal myocardial infarction, stent thrombosis, target vessel revascularization (TVR), stoke and bleeding was compared between Triple therapy group and Double therapy group.Results: The medication in Double therapy group included aspirin+ticagrelor, aspirin+clopidogrel, clopidogrel+warfarin and cilostazol+clopidogrel; in Triple therapy group was aspirin+clopidogrel+warfarin. Patient with HAS-BLED score≥3 was defined as high risk of bleeding and they were all treated by double therapy; HAS-BLED<3 was defined as low risk of bleeding, only 5.03％ patients were treated by triple therapy. 3 patients in Triple therapy group and 33 in Double therapy group suffered from gastrointestinal bleeding, P=0.338; 6 patients in Triple therapy group and 128 in Double therapy group had MACCE, P=0.589; 3 and 80 patients died in Triple therapy group and Double therapy group, P=0.766. Conclusion: Triple therapy was rarely used in elderly AF and ACS patients after stent implantation, double therapy was the main strategy; the incidence of MACCE and mortality were similar between triple and double therapies; patients with triple therapy had the higher incidence of gastrointestinal bleeding.

BACKGROUNDIt is well known that increased cumulative ventricular pacing proportion (CumVP%) is one of the most important causes for adverse cardiovascular events. Therefore, how to reduce CumVP% has been a treatment issue in recent years. This study aimed to investigate the effects of different pacing algorithms on CumVP% in patients with pacemakers.

METHODSPacemakers with three pacing algorithms, i.e., conventional dual chamber rate adaptive pacing (DDDR), search atrioventricular conduction plus (SAV+) and managed ventricular pacing (MVP), were implanted in 42 patients including 41 with bradycardia arrhythmias and one with ventricular tachycardia. Pacemakers were programmed to work in conventional DDDR, SAV+ and MVP during the follow-up periods of the first, the second and the third month. In each pacing algorithm, the time percentages of four pacing and sense status including atrial sense-ventricular sense (AS-VS), atrial sense-ventricular pacing (AS-VP), atrial pacing-ventricular sense (AP-VS) and atrial pacing-ventricular pacing (AP-VP) were calculated. Cumulative ventricular pacing proportions were compared in the three pacing algorithms in the first, the second and the third month postoperatively.

RESULTSIn the DDDR algorithm AS-VS, AS-VP, AP-VS and AP-VP were 2.4%, 52.3%, 2.5% and 42.8% respectively, while in SAV+ they were 19.3%, 34.9%, 33.9% and 12.0%, in MVP they were 38.9%, 13.2%, 41.6% and 6.4%. In the above the DDDR, SAV+ and MVP algorithms, cumulative ventricular pacing proportions were 95.1%, 46.9% and 19.6%, respectively (P < 0.05) and the percentages of CumVP% < 40% in patients were 0, 23.8% and 95.2.0% (P < 0.05).

CONCLUSIONSCompared with the conventional DDDR algorithm, both SAV+ and MVP significantly reduced the CumVP%, especially the MVP algorithm. Patients may benefit from MVP algorithm due to reduced CumVP%.

Aged ; Algorithms ; Cardiac Pacing, Artificial ; methods ; Electrophysiology ; Female ; Heart Ventricles ; physiopathology ; Humans ; Male ; Middle Aged ; Pacemaker, Artificial

Objective To study the preventing effect of oxygen enriched environment at physiological equivalent altitudes on high altitude pulmonary edema (HAPE) by HAPE animal model Methods Fifty male Wistar rats were randomly and averagely divided into ground control group,hypoxia group,oxygen enrichment group 1,oxygen enrichment group 2 and oxygen enrichment group 3.Groups were exposed to 6000 m with the climbing rate of 10 m/s in altitude chamber,except ground control group.Meanwhile,hypoxia group was supplied with air and oxygen enrichment group 1 and 2 were supplied with gas that contained 35％ and 30％ oxygen respectively.Oxygen enrichment group 3 was alternatively supplied with air or gas that contain 35 ％ oxygen every 4 h with the flow rate of 7 L/min.The chamber was descended to ground level after 24 h experiment.The water ratio of the left lung of rat was examined,the prefrontal lobe of right lung was taken for pathological observing,the middle and posterior lobe of the right lung were taken to detect the concentration of endothelin-1 (ET-1) and nitricoxide synthase (NOS) activity respectively. Results The water ratio of lung among every group presented significant difference.Ground control group showed the lowest water ratio (0.80％± 0.01％) and significantly different with that of other groups (P＜0.01).The water ratio of hypoxia group was 0.83％ + 0.01％,which was significantly higher than that of ground control group and oxygen enrichment group 3 (P＜0.01).The water ratio of rich oxygen group 2 was 0.81％ + 0.01％,which was obviously lower than that of oxygen enrichment group 1 and oxygen enrichment group 3 (P＜0.05).The pathology result showed that the rat lung of all the experiment groups presented severe to mild changes of interstitium pulmonary edema with the sequence of hypoxia group,oxygen enrichment group 2,oxygen enrichment group 1 and oxygen enrichment group 3.And there were no significant ET-1 concentration difference among every group. The NOS activity of ground control group was (1.49±0.24) U/mg,which was the highest in groups (P＜0.01),and the NOS activity of hypoxia group was (0.78 + 0.28) U/mg,which was the lowest among all groups (P＜0.01).Compared with the hypoxia group,the NOS activity of oxygen enrichment group 1 and oxygen enrichment group 3 was more energetic [(1.06 + 0.17) U/mg,(1.09 + 0.20) U/mg,P＜0.01]. Conclusions Serious HAPE happens on the rats that stayed at 6000 m for 24 h.By making 35％ oxygen enriched environment (physiological equivalent altitude of 2500 m) or supplying with 70 mm Hg oxygen partial pressure of inspired air would effectively prevent rat from HAPE.But there is no significant protection effect by supplying with 30％ oxygen concentration (physiological equivalent altitude is 3500 m) or setting up 56 mm Hg oxygen partial pressure of inspired air.Intermittent supplement of 35％ oxygen every 4 h would also effectively prevent rat from HAPE at 6000 m.

Objective To study the preventing effect of oxygen enriched environment at physiological equivalent altitudes on high altitude pulmonary edema (HAPE) by HAPE animal model Methods Fifty male Wistar rats were randomly and averagely divided into ground control group,hypoxia group,oxygen enrichment group 1,oxygen enrichment group 2 and oxygen enrichment group 3.Groups were exposed to 6000 m with the climbing rate of 10 m/s in altitude chamber,except ground control group.Meanwhile,hypoxia group was supplied with air and oxygen enrichment group 1 and 2 were supplied with gas that contained 35％ and 30％ oxygen respectively.Oxygen enrichment group 3 was alternatively supplied with air or gas that contain 35 ％ oxygen every 4 h with the flow rate of 7 L/min.The chamber was descended to ground level after 24 h experiment.The water ratio of the left lung of rat was examined,the prefrontal lobe of right lung was taken for pathological observing,the middle and posterior lobe of the right lung were taken to detect the concentration of endothelin-1 (ET-1) and nitricoxide synthase (NOS) activity respectively. Results The water ratio of lung among every group presented significant difference.Ground control group showed the lowest water ratio (0.80％± 0.01％) and significantly different with that of other groups (P＜0.01).The water ratio of hypoxia group was 0.83％ + 0.01％,which was significantly higher than that of ground control group and oxygen enrichment group 3 (P＜0.01).The water ratio of rich oxygen group 2 was 0.81％ + 0.01％,which was obviously lower than that of oxygen enrichment group 1 and oxygen enrichment group 3 (P＜0.05).The pathology result showed that the rat lung of all the experiment groups presented severe to mild changes of interstitium pulmonary edema with the sequence of hypoxia group,oxygen enrichment group 2,oxygen enrichment group 1 and oxygen enrichment group 3.And there were no significant ET-1 concentration difference among every group. The NOS activity of ground control group was (1.49±0.24) U/mg,which was the highest in groups (P＜0.01),and the NOS activity of hypoxia group was (0.78 + 0.28) U/mg,which was the lowest among all groups (P＜0.01).Compared with the hypoxia group,the NOS activity of oxygen enrichment group 1 and oxygen enrichment group 3 was more energetic [(1.06 + 0.17) U/mg,(1.09 + 0.20) U/mg,P＜0.01]. Conclusions Serious HAPE happens on the rats that stayed at 6000 m for 24 h.By making 35％ oxygen enriched environment (physiological equivalent altitude of 2500 m) or supplying with 70 mm Hg oxygen partial pressure of inspired air would effectively prevent rat from HAPE.But there is no significant protection effect by supplying with 30％ oxygen concentration (physiological equivalent altitude is 3500 m) or setting up 56 mm Hg oxygen partial pressure of inspired air.Intermittent supplement of 35％ oxygen every 4 h would also effectively prevent rat from HAPE at 6000 m.

BACKGROUNDMutations in the fibrillin-1 gene have been identified in patients with Marfan syndrome (MFS). This study aimed to identify the molecular defects in the fibrillin-1 gene in a Chinese family with Marfan syndrome, accompanied by aortic aneurysms/dissection.

METHODSTwo patients and one non-carrier in the family underwent complete physical, ophthalmic, and cardiovascular examinations. Genomic DNA was extracted from leukocytes of venous blood of these individuals in the family as well as 50 healthy normal controls. Polymerase chain reaction amplification and direct sequencing of all 65 coding exons of fibrillin-1 gene were analyzed.

RESULTSWe found a novel mutation (c.8547T > G, p.Tyr2849X) in exon 65 of fibrillin-1 gene in a Chinese proband with Marfan syndrome, accompanied by aortic aneurysms/dissection. Sudden death at a young age of affected members was seen due to aortic aneurysms/dissection. By evaluating genotype-phenotype correlations of patients with mutations in the 3' end of fibrillin-1 gene (exons 64 and 65), we also found that the presence of nonsense mutations occurring in exons 64 and 65 appeared to be an indicator of early-onset aortic risk and sudden death.

CONCLUSIONSThese results expand the mutation spectrum of fibrillin-1 gene and help in the study of the molecular pathogenesis of Marfan syndrome, indicating that mutations occurring in the 3' end of fibrillin-1 gene may play an independent functional role in the pathogenesis of Marfan syndrome.

Adult ; Female ; Fibrillin-1 ; Fibrillins ; Genotype ; Humans ; Male ; Marfan Syndrome ; etiology ; genetics ; Microfilament Proteins ; genetics ; Middle Aged ; Mutation ; Phenotype

Background and Objective: As a prospective vaccine carrier,nanoparticles can protect antigens from degradation and enhance immune response.This study prepared nanovaccines with MAGE-3-derived CD4+CD8+T cell epitope peptides,and investigated its character and antitumor effects on transplanted gastric cancer in mice.Methods: We adopted the self-assembly method to prepare peptide/chitosan conjugated with deoxycholic acid(chitosan-deoxycholic acid)nanoparticles.We observed the appearance of the chitosan-deoxycholic acid nanoparticles through a transmission electron microscope(TEM)and analyzed the peptide content and its release pattern by fluorescence spectrophotometry.We observed tumor-suppression efficacy in vivo through animal experiments.Results: We successfully prepared nanoparticles with MAGE-3 peptide antigen,and its encapsulation efficiency and loading level were about 37% and 17.0%,respectively.These nanoparticles presented a delayed release pattern in phosphate buffered saline(PBS)at pH 7.4,and the full release time was about 48 h.In 2 mg/mL lysozyme,the nanoparticles showed a sudden release,and the full release time was about 24 h.ELISPOT and cytotoxic experiments showed that the MAGE-3 peptide loaded nanoparticles could stimulate immune response in vivo and could generate MAGE-3-targeted cytotoxic T lymphocytes(CTLs),and kill MAGE-3-specific tumor cells.Tumor suppression experiments showed that the regression ratio of the peptide-loaded nanoparticles group was 37.81%.Conclusion: MAGE-3 peptide/chitosan-deoxycholic acid vaccine-loaded nanoparticles can stimulate antitumor immune response in vivo and can regress the growth of mouse forestomach carcinoma cell line MFC.