Rare diseases still lack effective treatments, and the development of drugs for rare diseases (known as orphan drugs) is an urgent medical problem. As natural active ingredients in living organisms, some biomacromolecule drugs have good biocompatibility, low immunogenicity, and high targeting. They have become one of the most promising fields in drug research and development in the 21st century. However, there are still many obstacles in terms of in vivo delivery. In view of the unique advantages of nanocarriers prepared from polymers, lipids, organic biomimetic and inorganic materials in drug delivery, researchers are committed to building an efficient delivery system with versatility and synergy to solve the bottleneck issues in treating rare diseases with biomacromolecule drugs. Therefore, this article reviews the research progress of nanocarrier delivering proteins, peptides and nucleic acids in the field of rare disease treatment in the past ten years, which provides ideas for researches on biomacromolecule drug nanosystems in the field of treatment of rare diseases.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood-brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).

OBJECTIVE: To observe the clinical effect of moxibustion with deqi on Alzheimer's disease (AD) rats, and evaluate its effect on β-amyloid (Aβ) transport and enzymatic degradation proteins, to explore its molecular mechanism for improving cognitive function. METHODS: Sixty SPF-grade male SD rats were randomly divided into a blank group (8 rats), a sham-operation group (8 rats) and a model establishment group (44 rats). The rats in the model establishment group were injected with Aβ₁-₄₂ at bilateral ventricles to establish AD model. Among the 38 rats with successful model establishment, 8 rats were randomly selected as the model group, and the remaining rats were treated with mild moxibustion at "Dazhui" (GV 14), once a day, 40 min each time, for 28 days. According to whether deqi appeared and the occurrence time of deqi, the rats were divided into a deqi group (12 rats), a delayed deqi group (10 rats) and a non-deqi group (8 rats). After the intervention, the Morris water maze test was applied to evaluate the cognitive function; the HE staining was applied to observe the brain morphology; the Western blot method was applied to measure the protein expression of Aβ and its receptor mediated transport [low-density lipoprotein receptor-related protein (LRP) 1, receptor for advanced glycation end products (RAGE), apolipoprotein E (ApoE)] and enzymatic degradation [neprilysin (NEP), insulin degrading enzyme (IDE), endothelin converting enzyme (ECE)-1 and angiotensin converting enzyme (ACE) 2]. RESULTS: Compared with the sham-operation group, in the model group, the escape latency was prolonged (P<0.01), and the times of platform crossing and the ratio of platform quadrant to total time were reduced (P<0.01); the brain tissue was seriously damaged; the expression of hippocampal Aβ and RAGE was increased (P<0.01), and the expression of hippocampal LRP1, ApoE, NEP, IDE, ECE-1 and ACE2 was decreased (P<0.01). Compared with the model group, the escape latency was shortened in the deqi group (P<0.05, P<0.01), and the escape latency in the delayed deqi group and the non-deqi group was shortened from Day 2 to Day 5 (P<0.05, P<0.01), and the times of platform crossing and the ratio of platform quadrant to total time were increased in the deqi group and the delayed deqi group (P<0.01, P<0.05); the brain damage in each moxibustion group was reduced, which was smallest in the deqi group, followed by the delayed deqi group and the non-deqi group; the expression of Aβ and RAGE was decreased (P<0.01, P<0.05) and the expression of LRP1 and IDE was increased in each moxibustion group (P<0.01, P<0.05); the expression of ApoE was increased in the deqi group and the delayed deqi group (P<0.01, P<0.05); the expression of NEP was increased in deqi group (P<0.05), and the expression of ECE-1 and ACE2 was increased in the deqi group and the delayed deqi group (P<0.05). Compared with the delayed deqi group and the non-deqi group, the escape latency in the deqi group was shortened from Day 3 to Day 5 (P<0.05), and the times of platform crossing and the ratio of platform quadrant to total time were increased (P<0.05, P<0.01). Compared with the non-deqi group, the expression of Aβ was reduced (P<0.05), the expression of LRP1 and ApoE was increased in the deqi group (P<0.05). The expression of NEP in the deqi group was higher than that in the delayed deqi group and the non-deqi group (P<0.05). CONCLUSION Compared with non-deqi, moxibustion with deqi could promote Aβ transport and degradation, thereby reducing Aβ level in the brain and improving cognitive function for AD rats.
Alzheimer Disease/therapy* ; Amyloid beta-Peptides/genetics* ; Angiotensin-Converting Enzyme 2 ; Animals ; Apolipoproteins E/metabolism* ; Hippocampus/metabolism* ; Male ; Moxibustion ; Rats ; Rats, Sprague-Dawley

Objective:To investigate the safety of early whole body computed tomography (WBCT) combined with coronary angiography (CAG) in patients with extracorporeal cardiopulmonary resuscitation (ECPR) and its application value in the diagnosis of cardiac arrest and complications of cardiopulmonary resuscitation (CPR).Methods:This was a retrospective study. Patients who underwent ECPR in the Emergency Department of the First Affiliated Hospital of Nanjing Medical University from January 2017 to July 2021 were enrolled in this research. Patients younger than 18 years or with incomplete clinical data were excluded. The results of WBCT and CAG examinations after ECPR were collected.Results:A total of 89 patients with ECPR, aged (47±17) years, were enrolled in the study, all underwent WBCT examination, and no adverse events such as ECMO and tracheal tube shedding occurred. WBCT found 7 cases of pulmonary embolism, 3 cases of aortic dissection and 2 cases of cerebral hemorrhage. WBCT identified CPR-related complications in 42 cases, including rib fractures ( n=20), pneumothorax ( n=5), mediastinal emphysema ( n=5), subcutaneous emphysema ( n=6), and hematoma or swelling at puncture site ( n=6). Fifty-five patients underwent CAG examination, the most common culprit vessels were the left anterior descending branch disease (58.2%) followed by the left circumflex branch disease (27.3%), the right coronary artery disease (21.8%) and left main artery disease (12.7%). Conclusions:Early WBCT and CAG examinations are of great significance and safety for the guidance of treatment in ECPR patients.

Ischemic dysfunction is an important global health problem. Vascular endothelial cells(VECs) play a key role in angiogenesis, and insufficient vascular remodeling may lead to chronic nonhealing wounds. Therefore, effective VEC generation strategies of exploration help improve angiogenesisin damaged tissues. Embryonic stem cells (ESCs) are widely used in the study of tissueendothelialization, and endothelial progenitor cells (EPCs) are indispensable parts of the development ofVECs. The aims of this study were to find a rapid, easily screened and reproducible method for thederivation of EPCs from mouse embryonic stem cells (mESCs), and obtain VECs with high survival ratesand strong functions from the directed differentiation of the EPCs. The results showed that mESCs weredifferentiated into " stepping stone" -like progenitor cells with active proliferative ability by 10 ng / mLVEGF and 5 ng / mL bFGF. At the same time, the method of differential adherence was helpful for theselection of EPCs, and EPCs induced high expression of CD133 and CD34 (The relative expressionlevels were 0. 88 ± 0. 04 and 2. 12 ± 0. 02, respectively) for 3 days. Then EPCs were digested withacctuse enzymes, and induced to differentiate into vascular endothelial-like cells by 50 ng / mL VEGF and25 ng / mL bFGF for 7 days. The endothelial cells not only expressed endothelial marker genes (CD31, CD144, LAMA5, Tek, KDR and vWF),and marker proteins CD31, CD144 and LAMA5 (The relativeexpression levels were 1. 07 ± 0. 03, 0. 60 ± 0. 02 and 0. 70 ± 0. 02, respectively), but also had thegood ability of migration, tubulogenesis and formation of W-P bodies. Moreover, PBS, EPC and VECwere used to treat wounds of the same size. Both EPC and VEC could accelerate the degree of tissuehealing (The relative healing rates were 78. 93 ± 75. 35%, 95. 57 ± 83. 73% and 100. 00 ± 0. 00%, respectively), and VEC significantly enhanced the ability of wound angiogenesis and inflammatoryresponses. In consequence, this study preliminarily confirmed that mESC-derived EPCs coulddifferentiate into VECs after directional induction for 7 days, which had good function of tissue repair. The physiological pathway on stem cells by stimulating angiogenesis is expected to become a new target fortissue remodeling.

In the past 37 years, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has undergone various major transmission routes in China, with the world most complex co-circulating HIV-1 subtypes, even the prevalence is still low. In response to the first epidemic outbreak of HIV in injecting drug users and the second one by illegal commercial blood collection, China issued the Anti-Drug Law and launched the Blood Donation Act and nationwide nucleic acid testing, which has avoided 98,232 to 211,200 estimated infections and almost ended the blood product-related infection. China has been providing free antiretroviral therapy (ART) since 2003, which covered >80% of the identified patients and achieved a viral suppression rate of 91%. To bend the curve of increasing the disease burden of HIV and finally end the epidemic, China should consider constraining HIV spread through sexual transmission, narrowing the gaps in identifying HIV cases, and the long-term effectiveness and safety of ART in the future.
Acquired Immunodeficiency Syndrome/prevention & control* ; China/epidemiology* ; Disease Outbreaks ; HIV Infections/prevention & control* ; Humans ; Prevalence

Objective: To assess the feasibility of HEAD-US scale in the clinical application of hemophilic arthropathy (HA) and propose an optimized ultrasound scoring system. Methods: From July 2015 to August 2017, 1 035 joints ultrasonographic examinations were performed in 91 patients. Melchiorre, HEAD-US (Hemophilic Early Arthropathy Detection with UltraSound) and HEAD-US-C (HEAD-US in China) scale scores were used respectively to analyze the results. The correlations between three ultrasound scales and Hemophilia Joint Health Scores (HJHS) were evaluated. The sensitivity differences of the above Ultrasonic scoring systems in evaluation of HA were compared. Results: All the 91 patients were male, with median age of 16 (4-55) years old, including 86 cases of hemophilia A and 5 cases hemophilia B. The median (P₂₅, P₇₅) of Melchiorre, HEAD-US and HEAD-US-C scores of 1 035 joints were 2(0,6), 1(0,5) and 2(0,6), respectively, and the correlation coefficients compared with HJHS was 0.747, 0.762 and 0.765 respectively, with statistical significance (P<0.001). The positive rates of Melchiorre, HEAD-US-C and HEAD-US scale score were 63.0% (95%CI 59.7%-65.9%), 59.5% (95%CI 56.5%-62.4%) and 56.6% (95%CI 53.6%-59.6%) respectively, and the difference was statistically significant (P<0.001). Even for 336 cases of asymptomatic joints, the positive rates of Melchiorre, HEAD-US-C and HEAD-US scale score were 25.0% (95%CI 20.6%-29.6%), 17.0% (95%CI 12.6%-21.1%) and 11.9% (95%CI 8.4%-15.7%) respectively, and the difference was statistically significant (P<0.001). There were significant changes (P<0.05) in the ultrasonographic score of HA before and after onset of hemorrhage in 107 joints of 40 patients. The difference in variation amplitude of HEAD-US-C scores and HEAD-US scores before and after joint bleeding was statistically significant (P<0.001). Conclusion: Compared with Melchiorre, there were similar good correlations between HEAD-US, HEAD-US-C and HJHS. HEAD-US ultrasound scoring system is quick, convenient and simple to use. The optimized HEAD-US-C scale score is more sensitive than HEAD-US, especially for patients with HA who have subclinical state, which make up for insufficiency of sensitivity in HEAD-US scoring system.
Adolescent ; Adult ; Child ; Child, Preschool ; China ; Hemarthrosis ; Hemophilia A ; Hemophilia B ; Humans ; Male ; Middle Aged ; Ultrasonography ; Young Adult

OBJECTIVETo investigate the effect of premature rupture of the membrane (PROM) on neonatal complications in premature infants.

METHODSThe registration information of 7684 preterm infants with gestational age <37 weeks were collected from the cooperative units in the task group between January 1, 2014 to December 31, 2014. Specially trained personnel from each cooperative units filled in the unified form in a standardized format to record the gender, gestational age, birth weight, PROM, placental abruption, antenatal corticosteroid, Apgar score, amniotic fluid pollution, and complications of the infants. The data were analyzed comparatively between the cases with PROM and those without (control).

RESULTSThe preterm mortality rate was significantly lower but the incidences of ICH, NEC, ROP and BPD were significantly higher in PROM group than in the control group (P<0.05). The 95% confidence interval of the OR value was <1 for mortality, and was >1 for ICH, NEC, ROP and BPD. After adjustment for gestational age, birth weight, gender, mode of delivery, placental abruption, placenta previa, prenatal hormones, gestational diabetes mellitus (GDM), gestational period hypertension and 5-min Apgar score <7, the incidences of NEC, ROP and BPD were significantly different between the two groups (P<0.05) with 95% confidence interval of OR value >1, but the mortality rate and incidence of ICH were not significantly different between the two groups (P>0.05).

CONCLUSIONPROM is a risk factor for NEC, ROP and BPD in preterm infants, and adequate intervention of PROM can reduce the incidences of such complications as NEC, ROP and BPD in the infants.

Apgar Score ; Birth Weight ; Female ; Fetal Membranes, Premature Rupture ; pathology ; Gestational Age ; Humans ; Incidence ; Infant, Newborn ; Infant, Newborn, Diseases ; etiology ; Infant, Premature ; Pregnancy ; Risk Factors

OBJECTIVETo investigate the Th17 cell and Treg cell levels in patients with sarcoidosis, and their relation to disease activation and glucocorticoids treatment.

METHODSTwenty-three sarcoidosis patients admitted in Yinzhou People's Hospital from January 2009 to December 2013 and 25 healthy subjects (controls) were included in this study. The blood samples and bronchoalveolar lavage fluid (BALF) samples were collected in all patients before and after glucocorticoids treatment. The serum angiotensin converting enzyme (SACE) levels were detected. The percentages of Th17 cells and Treg cells in peripheral blood and BALF were determined by flow cytometry, the concentrations of cytokines in serum and supernatants of BALF were measured by enzyme-linked immunosorbent assay (ELISA). The levels of ROR-γt and Foxp3 mRNA transcripts in peripheral blood mononuclear cells (PBMC) were determined by real-time quantitative PCR. The potential correlation between the percentages of Th17 or Treg cells and SACE levels was evaluated.

RESULTSCompared with healthy controls, significantly higher frequencies of Th17 cells (4.34%±0.89% vs 1.60% ± 0.42%), lower frequencies of Treg cells (1.28% ± 0.37% vs 3.39% ± 0.50%) in peripheral blood were observed. Higher level of ROR-γt mRNA (21.31 ± 3.55 vs 3.63 ± 1.00) and lower level of Foxp3 mRNA (1.60 ± 0.24 vs 3.12 ± 0.76) in peripheral blood were detected in sarcoidosis patients in active stage (before glucocorticoids treatment) (all P<0.01). After the treatment of glucocorticoids, these index in peripheral blood were significantly improved (Th17 cells 2.16% ± 0.68%，Treg cells 2.21% ± 0.42%, ROR-γt mRNA 10.15 ± 1.93, Foxp3 mRNA 2.44 ± 0.38) ( all P<0.05). The changing trends of Th17 and Treg cell cytokines levels in serum were consistent with two type cells. Meanwhile, the changing trends of above index in BALF of patients treated by glucocorticoids were consistent with those in sarcoidosis patients in active stage. The increased ratios of Th17 cells to Treg cells were positively correlated with the level of serum SACE (r= 0.781).

CONCLUSIONThe imbalance of Th17 cells and Treg cells in peripheral blood and airway may be involved in the pathogenesis of sarcoidosis, which was associated with the activity of disease, and the treatment of glucocorticoids may achieve a therapeutic effect by correcting the immune imbalance.

Bronchoalveolar Lavage Fluid ; Case-Control Studies ; Cytokines ; immunology ; Enzyme-Linked Immunosorbent Assay ; Forkhead Transcription Factors ; metabolism ; Humans ; Leukocytes, Mononuclear ; metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; metabolism ; Sarcoidosis ; immunology ; T-Lymphocytes, Regulatory ; immunology ; Th17 Cells ; immunology

Objective:To investigate the Th17 cell and Treg cell levels in patients with sarcoidosis , and their relation to disease activation and glucocorticoids treatment . Methods:Twenty-three sarcoidosis patients admitted in Yinzhou People's Hospital from January 2009 to December 2013 and 25 healthy subjects ( controls ) were included in this study .The blood samples and bronchoalveolar lavage fluid ( BALF) samples were collected in all patients before and after glucocorticoids treatment . The serum angiotensin converting enzyme (SACE) levels were detected.The percentages of Th17 cells and Treg cells in peripheral blood and BALF were determined by flow cytometry , the concentrations of cytokines in serum and supernatants of BALF were measured by enzyme-linked immunosorbent assay (ELISA).The levels of ROR-γt and Foxp3 mRNA transcripts in peripheral blood mononuclear cells ( PBMC) were determined by real-time quantitative PCR .The potential correlation between the percentages of Th 17 or Treg cells and SACE levels was evaluated . Results: Compared with healthy controls , significantly higher frequencies of Th17 cells (4.34%±0.89%vs 1.60%±0.42%), lower frequencies of Treg cells (1.28%±0.37% vs 3.39%±0.50%) in peripheral blood were observed.Higher level of ROR-γt mRNA (21.31 ±3.55 vs 3.63 ±1.00) and lower level of Foxp3 mRNA (1.60 ±0.24 vs 3.12 ±0.76) in peripheral blood were detected in sarcoidosis patients in active stage ( before glucocorticoids treatment ) ( all P<0 .01 ) .After the treatment of glucocorticoids , these index in peripheral blood were significantly improved (Th17 cells 2.16%±0.68%,Treg cells 2.21%±0.42%, ROR-γt mRNA 10.15 ±1.93, Foxp3 mRNA 2.44 ±0.38) ( all P <0.05).The changing trends of Th 17 and Treg cell cytokines levels in serum were consistent with two type cells.Meanwhile, the changing trends of above index in BALF of patients treated by glucocorticoids were consistent with those in sarcoidosis patients in active stage .The increased ratios of Th17 cells to Treg cells were positively correlated with the level of serum SACE (r=0.781).Conclusion:The imbalance of Th17 cells and Treg cells in peripheral blood and airway may be involved in the pathogenesis of sarcoidosis , which was associated with the activity of disease , and the treatment of glucocorticoids may achieve a therapeutic effect by correcting the immune imbalance .