Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immu-notherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histo-compatibility complex(MHC)class Ⅰ and Ⅱ antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4+and CD8+T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.

Objective: To explore the composition of intestinal microflora prior to onset of necrotizing enterocolitis (NEC) in very low birth weight preterm infants. Methods: This was a multicenter prospective nested case-control study. A total of 46 very low birth weight preterm infants (birth weight <1 500 g and gestional age <35 weeks) within 24 h of life admitted into Neonatal Intensive Care Unit of Children's Hospital of Soochow University and Suzhou Municipal Hospital from April 20 to November 20, 2018 were enrolled. Baseline clinical data and fecal samples of these infants were collected. The subsequent sampling time points were 1st, 4th and 7th day in the first week of life then once per week consecutively. The endpoint of sampling was NEC occurrence, patient discharge or the 8th week post-discharge, whichever came first. Fecal samples were analyzed by 16 S rDNA high-throughput nucleotide sequencing. The control cases were infants without NEC who were matched to the NEC cases with a ratio of 1∶1. The operational taxonomic units (OTU), sequence number and shannon diversity index of the fecal samples were analyzed. Continuous variables were compared with t-test or non-parametric test, and χ² test or Fisher's exact test was used for categorical variables. Results: There were 23 patients in each group. The gestational age was (29.4±1.8) weeks in NEC group and (29.9±1.6) weeks in control group, including 13 males (57%) and 11 males (48%) in each group, respectively. Species abundance showed that the Firmicutes in both groups decreased temporarily at 7 days of age and then increased with age in control group, but not in NEC group, the Proteobacteria in both groups increased at 7 days of age and then decreased in control group, but kept increasing in NEC group. Regarding the other levels of taxonomy, compared with that of the control group, the NEC group had lower abundance of Proteobacteria, γ-proteobacteria and Enterobacteriaceae at 7 days of age, while higer abundance of Faecalibacterium at 14 days of age, meanwhile, lower Clostridium and Streptococcus at 21 days of age, lower Firmicutes, Clostridia and Clostridium perfringens and higher Proteobacteria and γ-proteobacteria at 28 days of age, these differences were all statistically significant (U=43.00, 43.00, 45.00, 80.00, 74.00, 76.00, 19.00, 8.00, 36.00, 25.00, 25.00,all P<0.05). The shannon index of NEC group was both lower than that of the controls at 21 days of age (2.4 (1.4, 3.0) vs. 3.1 (2.6, 4.0), U=67.00, P=0.027) and 28 days of age (2.4 (1.4, 2.8) vs. 3.9 (3.3, 4.2), U=12.00, P=0.001). Conclusions: The intestinal microflora profile of very low birth weight preterm infants has already changed prior to NEC development. The emergence of differential flora and the reduction of microflora diversity may facilitate early identification and prevention of NEC.
Aftercare ; Case-Control Studies ; Child ; Enterocolitis, Necrotizing/epidemiology* ; Gastrointestinal Microbiome ; Humans ; Infant ; Infant, Newborn ; Infant, Premature ; Infant, Very Low Birth Weight ; Male ; Patient Discharge ; Prospective Studies

OBJECTIVES: To investigate the incidence of extrauterine growth retardation (EUGR) and its risk factors in very preterm infants (VPIs) during hospitalization in China. METHODS: A prospective multicenter study was performed on the medical data of 2 514 VPIs who were hospitalized in the department of neonatology in 28 hospitals from 7 areas of China between September 2019 and December 2020. According to the presence or absence of EUGR based on the evaluation of body weight at the corrected gestational age of 36 weeks or at discharge, the VPIs were classified to two groups: EUGR group (n=1 189) and non-EUGR (n=1 325). The clinical features were compared between the two groups, and the incidence of EUGR and risk factors for EUGR were examined. RESULTS: The incidence of EUGR was 47.30% (1 189/2 514) evaluated by weight. The multivariate logistic regression analysis showed that higher weight growth velocity after regaining birth weight and higher cumulative calorie intake during the first week of hospitalization were protective factors against EUGR (P<0.05), while small-for-gestational-age birth, prolonged time to the initiation of total enteral feeding, prolonged cumulative fasting time, lower breast milk intake before starting human milk fortifiers, prolonged time to the initiation of full fortified feeding, and moderate-to-severe bronchopulmonary dysplasia were risk factors for EUGR (P<0.05). CONCLUSIONS It is crucial to reduce the incidence of EUGR by achieving total enteral feeding as early as possible, strengthening breastfeeding, increasing calorie intake in the first week after birth, improving the velocity of weight gain, and preventing moderate-severe bronchopulmonary dysplasia in VPIs.
Female ; Fetal Growth Retardation ; Gestational Age ; Hospitalization ; Humans ; Incidence ; Infant ; Infant, Newborn ; Infant, Premature ; Infant, Very Low Birth Weight ; Prospective Studies ; Risk Factors

OBJECTIVES: To explore the optimal maintenance dose of caffeine citrate for preterm infants requiring assisted ventilation and caffeine citrate treatment. METHODS: A retrospective analysis was performed on the medical data of 566 preterm infants (gestational age ≤34 weeks) who were treated and required assisted ventilation and caffeine citrate treatment in the neonatal intensive care unit of 30 tertiary hospitals in Jiangsu Province of China between January 1 and December 31, 2019. The 405 preterm infants receiving high-dose (10 mg/kg per day) caffeine citrate after a loading dose of 20 mg/kg within 24 hours after birth were enrolled as the high-dose group. The 161 preterm infants receiving low-dose (5 mg/kg per day) caffeine citrate were enrolled as the low-dose group. RESULTS: Compared with the low-dose group, the high-dose group had significant reductions in the need for high-concentration oxygen during assisted ventilation (P=0.044), the duration of oxygen inhalation after weaning from noninvasive ventilation (P<0.01), total oxygen inhalation time during hospitalization (P<0.01), the proportion of preterm infants requiring noninvasive ventilation again (P<0.01), the rate of use of pulmonary surfactant and budesonide (P<0.05), and the incidence rates of apnea and bronchopulmonary dysplasia (P<0.01), but the high-dose group had a significantly increased incidence rate of feeding intolerance (P=0.032). There were no significant differences between the two groups in the body weight change, the incidence rates of retinopathy of prematurity, intraventricular hemorrhage or necrotizing enterocolitis, the mortality rate, and the duration of caffeine use (P>0.05). CONCLUSIONS This pilot multicenter study shows that the high maintenance dose (10 mg/kg per day) is generally beneficial to preterm infants in China and does not increase the incidence rate of common adverse reactions. For the risk of feeding intolerance, further research is needed to eliminate the interference of confounding factors as far as possible.
Caffeine/therapeutic use* ; Citrates ; Humans ; Infant ; Infant, Newborn ; Infant, Premature ; Respiration, Artificial ; Retrospective Studies

Psoriasis is an autoimmune skin disease in which dendritic cells (DCs) trigger the progression of psoriasis by complex interactions with keratinocytes and other immune cells. In the present study, we aimed to load celastrol, an anti-inflammatory ingredient isolated from Chinese herbs, on mannosylated liposomes to enhance DC uptake as well as to induce DC tolerance in an imiquimod-induced psoriasis-like mouse model. Mannose was grafted onto liposomes to target mannose receptors on DCs. The results demonstrated that compared with unmodified liposomes, DCs preferred to take up more fluorescence-labeled mannosylated liposomes. After loading celastrol into mannose-modified liposomes, they effectively inhibited the expression of maturation markers, including CD80, CD86 and MHC-II, on DCs both in vitro and in vivo. Additionally, after intradermal injection with a microneedle, celastrol-loaded mannose-modified liposomes (CEL-MAN-LPs) achieved a superior therapeutic effect compared with free drug and celastrol-loaded unmodified liposomes in the psoriasis mouse model in terms of the psoriasis area and severity index, histology evaluation, spleen weight, and expression of inflammatory cytokines. In conclusion, our results clearly revealed that CEL-MAN-LPs was an effective formulation for psoriasis treatment and suggested that this treatment has the potential to be applied to other inflammatory diseases triggered by activated DCs.

Polydopamine (PDA) is a novel type of polymer synthesized inspired by adhesion proteins in mussels. It has been widely used in tumor-targeting drug delivery systems due to its natural advantages such as good biocompatibility, excellent photothermal conversion performance, adhesion, high chemical reactivity and multiple drug release response mechanisms. This review summarizes the applications of PDA-based tumor-targeting drug delivery in recent years, hoping to provide references for designing a more reasonable and effective PDA-based multifunctional collaborative tumor therapy platform.

Professor
Acupuncture ; Acupuncture Therapy ; Angina, Stable ; Combined Modality Therapy ; Humans ; Moxibustion

Additional sex combs-like 1 (ASXL1) interacts with BRCA1-associated protein 1 (BAP1) deubiquitinase to oppose the polycomb repressive complex 1 (PRC1)-mediated histone H2A ubiquitylation. Germline BAP1 mutations are found in a spectrum of human malignancies, while ASXL1 mutations recurrently occur in myeloid neoplasm and are associated with poor prognosis. Nearly all ASXL1 mutations are heterozygous frameshift or nonsense mutations in the middle or to a less extent the C-terminal region, resulting in the production of C-terminally truncated mutant ASXL1 proteins. How ASXL1 regulates specific target genes and how the C-terminal truncation of ASXL1 promotes leukemogenesis are unclear. Here, we report that ASXL1 interacts with forkhead transcription factors FOXK1 and FOXK2 to regulate a subset of FOXK1/K2 target genes. We show that the C-terminally truncated mutant ASXL1 proteins are expressed at much higher levels than the wild-type protein in ASXL1 heterozygous leukemia cells, and lose the ability to interact with FOXK1/K2. Specific deletion of the mutant allele eliminates the expression of C-terminally truncated ASXL1 and increases the association of wild-type ASXL1 with BAP1, thereby restoring the expression of BAP1-ASXL1-FOXK1/K2 target genes, particularly those involved in glucose metabolism, oxygen sensing, and JAK-STAT3 signaling pathways. In addition to FOXK1/K2, we also identify other DNA-binding transcription regulators including transcription factors (TFs) which interact with wild-type ASXL1, but not C-terminally truncated mutant. Our results suggest that ASXL1 mutations result in neomorphic alleles that contribute to leukemogenesis at least in part through dominantly inhibiting the wild-type ASXL1 from interacting with BAP1 and thereby impairing the function of ASXL1-BAP1-TF in regulating target genes and leukemia cell growth.

Chinese patent medicine prescriptions containing Jujubea Fructus in 2015 edition of Chinese Pharmacopoeia and the Composition Principles of Chinese Patent Drug were collected, and the characteristics of Chinese patent medicine containing Jujubea Fructus were analyzed by using data mining technology. Statistical software Excel 2019, Clementine 12.0 and SPSS 21.0 were used to conduct statistical analysis of conforming Chinese patent medicine prescriptions by means of frequency statistics, association rule analysis and cluster analysis. Finally, a total of 185 Chinese patent medicine prescriptions containing Jujubea Fructus were included in this study, involving 402 Chinese medicines and 28 kinds of high frequency Chinese medicines, with Jujubea Fructus, Poria, Zingiberis Rhizoma Recens, Glycyrrhizae Radix et Rhizoma, and Codonopsis Radix as the top five. The deficiency-nourishing drugs were in the most common efficacy classification, mainly sweet, bitter and pungent, with most medicine properties of warm and gentle, main meridians of spleen lung and stomach, dosage forms of pills, granules and tablets, and main indications of splenic diseases. Fifteen drug combinations were obtained in association rule analysis. Eleven drug combinations were obtained by association rule analysis of Chinese patent medicine containing Jujubea Fructus in the treatment of splenic diseases, and the drugs were divided into two categories by cluster analysis. According to the above analysis, it is found that the Chinese patent medicine prescriptions containing Jujubea Fructus are mainly composed of deficiency-nourishing drugs, mostly compatible with drugs of sweet, bitter and pungent flavors, warm and gentle properties, and spleen, lung, and stomach meridians in the treatment of splenic diseases, with Sijunzi Decoction as the main drug. This study provides guidance for modern clinical application and development of Jujubea Fructus.
China ; Data Mining ; Drugs, Chinese Herbal ; Medicine, Chinese Traditional ; Nonprescription Drugs

Psoriasis is an autoimmune inflammatory disease, where dendritic cells (DCs) play an important role in its pathogenesis. In our previous work, we have demonstrated that topical delivery of curcumin-loaded poly (lactic-