Left ventricular (LV) relaxation is an energy-dependent process and susceptible to disruption by various disease statuses. For assessment of LV relaxation, not only invasive methods but also ...noninvasive methods have been developed, such as digitized M mode echocardiogram, RNA, RVG, DTI, and cardiac cine CT or MRI. Recently, new techniques were developed to measure myocardial rotational movement, such as 2-dimensional STI, VVI, and harmonic phase-tagged MRI.
Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA ...vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD).
This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18–59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 μg, 10 μg, 15 μg, 20 μg, and 25 μg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212).
Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one 5% of 20 in the 5 μg group, 13 65% of 20 in the 10 μg group, 17 85% of 20 in the 15 μg group, 19 95% of 20 in the 20 μg group, 16 100% of 16 in the 25 μg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 μg group, three (15%) of 20 in the 10 μg group, six (30%) of 20 in the 15 μg group, seven (35%) of 20 in the 20 μg group, five (31%) of 16 in the 25 μg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 μg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19.
ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale.
National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.
Background and Objective:
Gastric cancer (GC) is a common tumor malignancy with high incidence and poor prognosis. Laminin is an indispensable component of basement membrane and extracellular matrix, ...which is responsible for bridging the internal and external environment of cells and transmitting signals. This study mainly explored the association of the LAMB1 expression with clinicopathological characteristics and prognosis in gastric cancer.
Methods:
The expression data and clinical information of gastric cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG). And we analyzed the relationship between LAMB1 expression and clinical characteristics through R. CIBERSORTx was used to calculate the absolute score of immune cells in gastric tumor tissues. Then COX proportional hazard models and Kaplan-Meier curves were performed to evaluate the role of LAMB1 and its influence on prognosis in gastric cancer patients. Finally, GO and KEGG analysis were applied for LAMB1-related genes in gastric cancer, and PPI network was constructed in Cytoscape software.
Results:
In the TCGA cohort, patients with gastric cancer frequently generated LAMB1 gene copy number variation, but had little effect on mRNA expression. Both in the TCGA and ACRG cohorts, the mRNA expression of LAMB1 in gastric cancer tissues was higher than it in normal tissues. All patients were divided into high expression group and low expression group according to the median expression level of LAMB1. The elevated expression group obviously had more advanced cases and higher infiltration levels of M2 macrophages. COX proportional hazard models and Kaplan-Meier curves revealed that patients with enhanced expression of LAMB1 have a worse prognosis. GO/KEGG analysis showed that LAMB1-related genes were enriched in PI3K-Akt signaling pathway, focal adhesion, ECM-receptor interaction, etc.
Conclusions:
The high expression of LAMB1 in gastric cancer is related to the poor prognosis of patients, and it may be related to microenvironmental changes in tumors.
Ovarian cancer is a common malignancy in the female reproductive system with a high mortality rate. The most important reason is multidrug resistance (MDR) of cancer chemotherapy. To reduce side ...effects, reverse resistance and improve efficacy for the treatment of ovarian cancer, a "core-shell" polymeric nanoparticle-mediated curcumin and paclitaxel co-delivery platform was designed.
Nuclear magnetic resonance confirmed the successful grafting of polyethylenimine (PEI) and stearic acid (SA) (PEI-SA), which is designed as a mother core for transport carrier. Then, PEI-SA was modified with hyaluronic acid (HA) and physicochemical properties were examined. To understand the regulatory mechanism of resistance and measure the anti-tumor efficacy of the treatments, cytotoxicity assay, cellular uptake, P-glycoprotein (P-gp) expression and migration experiment of ovarian cancer cells were performed. In addition, adverse reactions of nanoformulation to the reproductive system were examined.
HA-modified drug-loaded PEI-SA had a narrow size of about 189 nm in diameters, and the particle size was suitable for endocytosis. The nanocarrier could target specifically to CD44 receptor on the ovarian cancer cell membrane. Co-delivery of curcumin and paclitaxel by the nanocarriers exerts synergistic anti-ovarian cancer effects on chemosensitive human ovarian cancer cells (SKOV3) and multi-drug resistant variant (SKOV3-TR30) in vitro, and it also shows a good anti-tumor effect in ovarian tumor-bearing nude mice. The mechanism of reversing drug resistance may be that the nanoparticles inhibit the efflux of P-gp, inhibit the migration of tumor cells, and curcumin synergistically reverses the resistance of PTX to increase antitumor activity. It is worth noting that the treatment did not cause significant toxicity to the uterus and ovaries with the observation of macroscopic and microscopic.
This special structure of targeting nanoparticles co-delivery with the curcumin and paclitaxel can increase the anti-tumor efficacy without increasing the adverse reactions as a promising strategy for therapy ovarian cancer.
Summary Background The current influenza pandemic calls for a safe and effective vaccine. We assessed the safety and immunogenicity of eight formulations of 2009 pandemic influenza A H1N1 vaccine ...produced by ten Chinese manufacturers. Methods In this multicentre, double-blind, randomised trial, 12 691 people aged 3 years or older were recruited in ten centres in China. In each centre, participants were stratified by age and randomly assigned by a random number table to receive one of several vaccine formulations or placebo. The study assessed eight formulations: split-virion formulation containing 7·5 μg, 15 μg, or 30 μg haemagglutinin per dose, with or without aluminium hydroxide adjuvant, and whole-virion formulation containing 5 μg or 10 μg haemagglutinin per dose, with adjuvant. All formulations were produced from the reassortant strain X-179A (A/California/07/2009-A/PR/8/34). We analysed the safety (adverse events), immunogenicity (geometric mean titre GMT of haemagglutination inhibition antibody), and seroprotection (GMT ≥1:40) of the formulations. Analysis was by per protocol. Two sites registered their trial with ClinicalTrials.gov , numbers NCT00956111 and NCT00975572 . The other eight studies were registered with the State Food and Drug Administration of China. Findings 12 691 participants received the first dose on day 0, and 12 348 participants received the second dose on day 21. The seroprotection rate 21 days after the first dose of vaccine ranged from 69·5% (95% CI 65·9–72·8) for the 7·5 μg adjuvant split-virion formulation to 92·8% (91·9–93·6) for the 30 μg non-adjuvant split-virion formulation. The seroprotection rate was 86·5% (796 of 920; 84·1–88·7) in recipients of one dose of the 7·5 μg non-adjuvant split-virion vaccine compared with 9·8% (140 of 1432; 8·3–11·4) in recipients of placebo (p<0·0001). One dose of the 7·5 μg non-adjuvant split-virion vaccine induced seroprotection in 178 of 232 children (aged 3 years to <12 years; 76·7%, 70·7–82·0), 211 of 218 adolescents (12 years to <18 years; 96·8%, 93·5–98·7), 289 of 323 adults (18–60 years; 89·5%, 85·6–92·6), and 118 of 147 adults older than 60 years (80·3%, 72·9–86·4), meeting the European Union's licensure criteria for seroprotection in all age-groups. In children, a second dose of the 7·5 μg formulation increased the seroprotection rate to 97·7% (215 of 220, 94·8–99·3). Adverse reactions were mostly mild or moderate, and self-limited. Severe adverse effects occurred in 69 (0·6%, 0·5–0·8) recipients of vaccine compared with one recipient (0·1%, 0–0·2) of placebo. The most common severe adverse reaction was fever, which occurred in 25 (0·22%; 0·14–0·33) recipients of vaccine after the first dose and four (0·04%; 0·01–0·09) recipients of vaccine after the second dose compared with no recipients of placebo after either dose. Interpretation One dose of non-adjuvant split-virion vaccine containing 7·5 μg haemagglutinin could be promoted as the formulation of choice against 2009 pandemic influenza A H1N1 for people aged 12 years or older. In children (aged <12 years), two 7·5 μg doses might be needed. Funding Sinovac Biotech, Hualan Biological Bacterin, China National Biotec Group, Beijing Tiantan Biological Products, Changchun Institute of Biological Products, Changchun Changsheng Life Sciences, Jiangsu Yanshen Biological Technology Stock, Zhejiang Tianyuan Bio-Pharmaceutical, Lanzhou Institute of Biological Products, Shanghai Institute of Biological Products, and Dalian Aleph Biomedical.
Chronic urticaria (CU) is a debilitating skin disease that lasts for more than 6 weeks with wheals and/or angioedema, including chronic spontaneous urticaria (CSU) and chronic inducible urticaria ...(CIndU). In China, the prevalence of this disease is high, more than 1%, and on the rise. CU has a major impact on the quality of life (QoL) of patients who frequently experience sleep disturbance, depression, and anxiety. Nearly one-third of patients with CSU, in China, are resistant to second-generation H1-antihistamines (sgAHs), even at a fourfold dose (second line; off-label). Omalizumab is approved for the treatment of CSU treatment in Europe and shows remarkable efficacy and safety. In China, regulatory approval for the use of omalizumab is pending, and its use in clinical practice varies widely. Consensus on omalizumab CU treatment in China is urgently needed. The aim of this article is to propose a practical omalizumab treatment algorithm for the management of antihistamine-resistant CSU and CIndU in adults and special population including children and adolescents, and pregnant or breast feeding women, to guide daily clinical practice in China. In the development of this consensus, an expert group including mainly dermatologists, allergists, but also pulmonologists, ENTs, immunologists, and pediatricians in Allergic Disease Prevention and Control Committee, Chinese Preventive Medicine Association, reviewed the existing evidence and developed consensus on the use of omalizumab in CU patients from China. The goal of this consensus is to assist clinicians in making rational decisions in the management of refractory CU with omalizumab. The key clinical questions covered by the treatment algorithm are: 1) Omalizumab treatment routine strategy in both CSU and CIndU patients; 2) Recommended dose and treatment duration for different age stratification; 3) Treatment duration for CU patients with other allergic comorbidities; 4) Recommendation on omalizumab stopping strategy.
BACKGROUNDMediastinal neoplasms are typical thoracic diseases with increasing incidence in the general global population and can lead to poor prognosis. In clinical practice, the mediastinum's ...complex anatomic structures and intertype confusion among different mediastinal neoplasm pathologies severely hinder accurate diagnosis. To solve these difficulties, we organised a multicentre national collaboration on the basis of privacy-secured federated learning and developed CAIMEN, an efficient chest CT-based artificial intelligence (AI) mediastinal neoplasm diagnosis system. METHODSIn this multicentre cohort study, 7825 mediastinal neoplasm cases and 796 normal controls were collected from 24 centres in China to develop CAIMEN. We further enhanced CAIMEN with several novel algorithms in a multiview, knowledge-transferred, multilevel decision-making pattern. CAIMEN was tested by internal (929 cases at 15 centres), external (1216 cases at five centres and a real-world cohort of 11 162 cases), and human-AI (60 positive cases from four centres and radiologists from 15 institutions) test sets to evaluate its detection, segmentation, and classification performance. FINDINGSIn the external test experiments, the area under the receiver operating characteristic curve for detecting mediastinal neoplasms of CAIMEN was 0·973 (95% CI 0·969-0·977). In the real-world cohort, CAIMEN detected 13 false-negative cases confirmed by radiologists. The dice score for segmenting mediastinal neoplasms of CAIMEN was 0·765 (0·738-0·792). The mediastinal neoplasm classification top-1 and top-3 accuracy of CAIMEN were 0·523 (0·497-0·554) and 0·799 (0·778-0·822), respectively. In the human-AI test experiments, CAIMEN outperformed clinicians with top-1 and top-3 accuracy of 0·500 (0·383-0·633) and 0·800 (0·700-0·900), respectively. Meanwhile, with assistance from the computer aided diagnosis software based on CAIMEN, the 46 clinicians improved their average top-1 accuracy by 19·1% (0·345-0·411) and top-3 accuracy by 13·0% (0·545-0·616). INTERPRETATIONFor mediastinal neoplasms, CAIMEN can produce high diagnostic accuracy and assist the diagnosis of human experts, showing its potential for clinical practice. FUNDINGNational Key R&D Program of China, National Natural Science Foundation of China, and Beijing Natural Science Foundation.
Abstract Background: Infantile spasms (IS) is an age-specific and severe epileptic encephalopathy that occurs in infancy and early childhood and is usually refractory to conventional antiepileptic ...drugs. Adrenocorticotropic hormone (ACTH) has been the treatment of choice for IS, but ACTH use has been associated with infection and hypertension. Magnesium ion is an N -methyl-D-aspartic acid (NMDA)-noncompetitive antagonist that might inhibit NMDA activity and has antiepileptic and neuroprotective effects. Objective: This study compared the efficacy and tolerability of ACTH + magnesium sulfate (MgS04 ) versus ACTH monotherapy for the treatment of IS. Methods: This 24-week, randomized, open-label follow-up study enrolled male and female infants with IS. Patients were randomly assigned to receive ACTH 25 U/d + MgS04 0.25 g/kg/d, or ACTH 25 U/d only (control), intravenously for 3 weeks. Efficacy was assessed over a period of 24 weeks based on seizure frequency, EEG, and Gesell testing of psychomotor skills (subscales: language, motor, adaptive, and personal-social skills; measured using a developmental quotient DQ ). Tolerability was assessed by monitoring for adverse events using laboratory analysis and clinical evaluation. Results: Thirty-eight infants were enrolled (23 male, 15 female; median age, 9.2 months; 19 patients per group). At 12 weeks, 14 patients (73.7%) who received ACTH + MgS04 and 9 patients (47.4%) in the control group were seizure free. At 24 weeks, seizurefree rates were 12 (63.2%) in the ACTH + MgS04 group and 10 (52.6%) in the control group. On EEG, 9 patients (47.4%) in the ACTH + MgSO4 group achieved complete recovery (normalized EEG), 5 (26.3 %) attained partial improvement (multifocal spike wave), and 5 (26.3%) had no improvement (hypsarrhythmia or modified hypsarrhythmia). At 4 weeks, in the control group, 5 patients (26.3 %) achieved complete recovery, 6 (31.6%) achieved partial improvement, and 8 (42.1%) had no improvement. Of the 12 patients who were seizure free at 24 weeks in the ACTH + MgS04 group, 11 (91.7%) had complete recovery (normalized EEG); this rate was 7 of 10 (70.0%) in the control group. In the ACTH + MgS04 group, the change from baseline to 24 weeks in mean (SD) personal-social DQ was significant (from 48.6 6.4 to 65.2 7.1, respectively; P < 0.05). In the control group, the difference before and after treatment was nonsignificant (47.7 6.0 vs 49.9 4.4). None of the other Gesell test findings were significant versus baseline. The most common AEs included upper respiratory tract infection and pyrexia (both, 3 15.8% per group); diarrhea (2 10.5% per group); and hypertension, insomnia, and irritability (all, 0 in the ACTH + MgS04 group and 2 10.5% in the control group). None of the between-group differences in the prevalences of AEs were significant between the 2 groups. Conclusions: In this study in infants with IS, the proportions of patients who were seizure free from 4 to 24 weeks were significantly greater in the ACTH + MgS04 group compared with the ACTH monotherapy group. Personal-social neurodevelopment was significantly improved from baseline in the group that received combination treatment. Both treatments were generally well tolerated.
Abstract Objectives Circulating chronic lymphocytic leukemia (CLL) cells appear not to be overly utilizing aerobic glycolysis. However, recurrent contact with CLL cells in a stromal microenvironment ...leads to increased aerobic glycolysis and the cells’ overall glycolytic capacity, which promotes cell survival and proliferation. TP53-induced glycolysis and apoptosis regulator(TIGAR) has been directly implicated in cellular metabolism in the control of glycolysis. TIGAR inhibits glycolysis and protects cells from intracellular reactive oxygen species (ROS)-associated apoptosis. Methods TIGAR mRNA expression was investigated by quantitative PCR in 102 newly diagnosed CLL patients. Furthermore, the relationship between the expression of TIGAR and its clinical characteristics and prognosis were investigated. Moreover, we also investigated the correlation between TIGAR expression and apoptosis in primary CLL cells. Results Our data revealed that TIGAR overexpression was correlated with the protection from spontaneous apoptosis in CLL cells, and is strongly associated with advanced Binet stage, unmutated immunoglobulin heavy-chain variable region ( IGHV ) status, CD38 positivity, β2-microglobulin and p53 aberrations. Higher expression of TIGAR was associated with shorter treatment-free survival (median: three months vs . 51 months, P = 0.0108), worse overall survival (median: 74 months vs . not reached, P = 0.0242), and the diverse responses to fludarabine-based chemotherapy. TIGAR expression in patients resistant to chemotherapy was significantly higher than in patients sensitive to chemotherapy (mean: 0.3859 ± 0.1710 vs. 0.0974 ± 0.0291, P = 0.0290). Conclusion Taken together, our findings revealed that high TIGAR expression is closely correlated with worse clinical outcome in CLL patients, and depicted how bioenergetic characteristics could be therapeutically exploited in CLL.
This study aimed to determine the appropriate body mass index (BMI)-dependent noise index (NI) setting in computed tomography pulmonary angiography (CTPA) with automatic tube current modulation with ...adaptive statistical iterative reconstruction (ASiR).
A total of 480 patients who had a CTPA were divided into group A (18.5 kg/m
≤ BMI < 25 kg/m
), group B (25 kg/m
≤ BMI < 30 kg/m
), and group C (BMI ≥ 30 kg/m
), according to their BMI values; each group had 160 patients. The three groups were further randomly divided into four subgroups: A1, A2, A3, A4; B1, B2, B3, B4; and C1, C2, C3, C4, with corresponding NI values of 26, 36, 40, and 46, respectively. All images were restructured with the ASiR algorithm, and the images with the lowest NI (26 Hounsfield units) in each group were used as reference standard. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) for the pulmonary artery of each group were calculated. Subjective image quality was evaluated using a five-score method by two independent radiologists. The CT dose index of volume and dose-length product were recorded and were converted to effective dose (ED). SNR and CNR in the group A, B, and C subgroups were compared to repeated measures analysis of variance, and the subjective score, Volumetric CT dose index of volume, dose-length product, and ED were compared to one-way analysis of variance.
For groups A and B, the SNR, CNR, and subjective scores of the images in their subgroups showed no statistical differences (P >.05). The ED in subgroups A4 and B4 was significantly lower than that in subgroups A1 (by 33.24%) and B1 (by 34.47%) (P <.01). For group C, there was no significant difference in the SNR, CNR, and the subjective image scores between subgroups C3 and C1 (P >.05). The ED in subgroup C3 was significantly lower than the ED in subgroup C1 (by 47.75%) (P <.01) CONCLUSIONS: Patient BMI-dependent NI settings that are higher than the recommended value may be used in CTPA with automatic tube current modulation and ASiR to effectively reduce radiation dose while maintaining diagnostic image quality.
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