With the widespread use of antibiotics, drug-resistant bacterial infections have become a significant threat to human health. Finding new antibacterial strategies that can effectively control drug-resistant bacterial infections has become an urgent task. Unlike small molecule drugs that target bacterial proteins, antisense oligonucleotide (ASO) can target genes related to bacterial resistance, pathogenesis, growth, reproduction and biofilm formation. By regulating the expression of these genes, ASO can inhibit or kill bacteria, providing a novel approach for the development of antibacterial drugs. To overcome the challenge of delivering antisense oligonucleotide into bacterial cells, various drug delivery systems have been applied in this field, including cell-penetrating peptides, lipid nanoparticles and inorganic nanoparticles, which have injected new momentum into the development of antisense oligonucleotide in the antibacterial realm. This review summarizes the current development of small nucleic acid drugs, the antibacterial mechanisms, targets, sequences and delivery vectors of antisense oligonucleotide, providing a reference for the research and development of antisense oligonucleotide in the treatment of bacterial infections.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Background: s/Aims: Sarcomatoid hepatocellular carcinoma (HCC) is a rare histological subtype of HCC characterized by extremely poor prognosis; however, its molecular characterization has not been elucidated. Methods: In this study, we conducted an integrated multiomics study of whole-exome sequencing, RNA-seq, spatial transcriptome, and immunohistochemical analyses of 28 paired sarcomatoid tumor components and conventional HCC components from 10 patients with sarcomatoid HCC, in order to identify frequently altered genes, infer the tumor subclonal architectures, track the genomic evolution, and delineate the transcriptional characteristics of sarcomatoid HCCs. Results: Our results showed that the sarcomatoid HCCs had poor prognosis. The sarcomatoid tumor components and the conventional HCC components were derived from common ancestors, mostly accessing similar mutational processes. Clonal phylogenies demonstrated branched tumor evolution during sarcomatoid HCC development and progression. TP53 mutation commonly occurred at tumor initiation, whereas ARID2 mutation often occurred later. Transcriptome analyses revealed the epithelial–mesenchymal transition (EMT) and hypoxic phenotype in sarcomatoid tumor components, which were confirmed by immunohistochemical staining. Moreover, we identified ARID2 mutations in 70% (7/10) of patients with sarcomatoid HCC but only 1–5% of patients with non-sarcomatoid HCC. Biofunctional investigations revealed that inactivating mutation of ARID2 contributes to HCC growth and metastasis and induces EMT in a hypoxic microenvironment. Conclusions We offer a comprehensive description of the molecular basis for sarcomatoid HCC, and identify genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment), that may contribute to the formation of the sarcomatoid tumor component through EMT, leading to sarcomatoid HCC development and progression.

Objective To investigate the effect of chemokine CXC ligand 9(CXCL9)on cognitive function impairment in patients with breast cancer brain metastases undergoing whole-brain radiotherapy(WBRT)using bioinformatics methods.Methods The mRNA of breast cancer brain metastases datasets GSE43837 and GSE12276 and Alzheimer's disease(AD)dataset GSE161199 were screened and downloaded from GEO database.Limma method and Venn diagrams were used to identify common differentially expressed genes(DEGs),and protein-protein interaction and functional prediction through GeneMANIA website assays were performed.A total of 42 patients with breast cancer brain metastases who first visited the Department of Radiotherapy at the First Affiliated Hospital of Hebei North University from January 2021 to January 2023 were selected.Patients were divided into normal cognitive function group and cognitive function impairment group based on cognitive status.Enzyme-linked immunosorbent assay(ELISA)was employed to detect serum CXCL9 levels one week before and three months after radiotherapy.The mini-mental state examination(MMSE)was used to assess patients'cognitive function.Results The DEGs from datasets GSE43837 and GSE12276 included PKP1,POLDIP2,SPAG5,ALDOC,PTPRZ1,PKIA,TLCD1,CPE,PMP22 and CXCL9.The DEGs from GSE161199 included RPS16,CD79A,LYPD3,RPL28,HBG2,RPL23AP7,TRNR,CXCL9.Venn diagram showed that CXCL9 was a common DEG between breast cancer brain metastasis and AD.Functional enrichment analysis indicated that CXCL9 was involved in cellular responses to chemokines,negative regulation of immune system processes,negative regulation of vascular morphogenesis,Toll-like receptor signaling pathway,nucleotide oligomerization domain(NOD)-like receptor signaling pathway,and JAK-STAT signaling pathway.Before radiotherapy,patients with cognitive function impairment and normal cognitive function accounted for 61.9%and 38.1%,respectively,with a statistically significant difference in MMSE scores[(24.53±2.19)vs.(28.89±1.36),P＜0.01].Compared with normal cognitive function group,patients with cognitive function impairment had a significantly increased number of brain metastases and significantly lower Karnofsky performance status(KPS)scores and serum CXCL9 levels(P＜0.05).Three months after radiotherapy,patients with cognitive function impairment and normal cognitive function accounted for 47.6%and 52.4%,respectively,with a statistically significant difference in MMSE scores[(25.16±1.98)vs.(28.18±1.08),P＜0.01].Compared with normal cognitive function group,patients with cognitive function impairment had significantly lower CXCL9 levels(P=0.003).In patients with normal cognitive function,CXCL9 levels were remarkably lower after radiotherapy compared to those before radiotherapy(P=0.009).Conclusions Patients with cognitive function impairment had significantly lower CXCL9 levels than those with normal cognitive function,and whole-brain radiotherapy may be related to a certain degree of reduction in CXCL9 levels.

Objective To develop a matrix metalloproteinase(MMP)-responsive hyaluronic acid(HA)-based controlled-release material for brain-derived neurotrophic factor(BDNF)to provide a novel therapeutic strategy for intervention and repair of traumatic brain injury(TBI).Methods HA was modified with amination,followed by condensation with Suflo-SMCC carboxyl group to form amide,and then linked with glutathione(GSH)to synthesize HA-GSH.The recombinant glutathione S-transferase(GST)-tissue inhibitor of metalloproteinase(TIMP)-BDNF(GST-TIMP-BDNF)expression plasmid was constructed using molecular cloning technique with double enzyme digestion by Bam H Ⅰ and Eco R Ⅰ.The recombinant GST-TIMP-BDNF protein was expressed in the Escherichia coli prokaryotic expression system,and purified by ion exchange chromatography,confirmed by Western blotting.MMP diluents were supplemented with PBS,MMP inhibitor marimastat,and varing concentrations(0.4,0.6,0.8 mg/ml)of GST-TIMP-BDNF or GST-BDNF.MMP-2 activity was analyzed using an MMP activity detection kit to evaluate the inhibitory effect of the recombinant protein on MMP.Primary rat neurons were extracted and cultured to establish an iron death model induced by RSL3.The effect of recombinant protein GST-TIMP-BDNF on neuronal injury was detected by immunofluorescence staining.Results MRI hydrogen spectrum identification confirmed the successful synthesis of HA-GSH.Western blotting results showed the successful expression of the recombinant protein GST-TIMP-BDNF containing the GST tag using the E.coli prokaryotic expression system.MMP activity detection results indicated that the recombinant protein GST-TIMP-BDNF had a superior inhibitory effect on MMP-2 activity compared to GST-BDNF(P<0.05).Immunofluorescence staining results showed a significant increase in fluorescence intensity in rat neurons treated with GST-TIMP-BDNF after RSL3 induction(P<0.05).Conclusion A MMP-responsive HA-based BDNF controlled-release material has been successfully developed,exhibiting a protective effect on neuron damage.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Objective:To compare thulium laser enucleation of the prostate(ThuLEP)with plasma kinetic resection of the prostate(PKRP)in the treatment of BPH.Methods:We retrospectively analyzed the medical records of 160 cases of BPH treated by ThuLEP(the observation group,n=80)or PKRP(the control group,n=80)in our hospital from January 2021 to December 2023.We recorded the operation time,bladder irrigation time,catheter retention time,hospitalization time,postoperative complica-tions,and pre-and postoperative maximum urinary flow rate(Qmax),residual urine volume(PVR),prostate-specific antigen(PSA)and prostate volume,followed by comparison of the data obtained between the two groups of patients.Results:Compared with the controls,the patients of the observation group showed significantly shorter operation time([67.25±7.24]vs[60.10±5.15]min,P<0.05),bladder irrigation time([46.90±10.77]vs[43.24±6.65]h,P<0.05),catheterization time([5.60±1.31]vs[5.03±1.24]d,P<0.05)and hospitalization time([7.31±2.00]vs[6.55±1.67]d,P<0.05),higher Qmax([18.50±1.24]vs[20.68±1.45]ml/s,P<0.05),lower PVR([12.10±3.53]vs[10.82±3.10]ml,P<0.05),PSA([4.60±0.78]vs[3.38±0.40]μg/L,P<0.05)and prostate volume([25.35±6.46]vs[20.12±5.13]ml,P<0.05)at 3 months after surgery,but no statistically significant difference in the total incidence of postoperative complications(7.50%[6/80]vs 5.00%[4/80],P>0.05).Conclusion:ThuLEP,with its advantages of notable effect,short operation and hospitaliza-tion time,significant improvement of urinary flow dynamics and prostate function,deserves clinical promotion for the treatment of BPH.

The pharmaceutical manufacturing model is gradually changing from intermittent manufacturing to continuous manufacturing and intelligent manufacturing. This paper briefly reviewed the supervision and research progress in continuous pharmaceutical manufacturing in China and abroad and described the definition and advantages of continuous pharmaceutical manufacturing. The continuous manufacturing of traditional Chinese medicine(TCM) at the current stage was summarized in the following three terms: the enhancement of the continuity of intermittent manufacturing operations, the integration of continuous equipment to improve physical continuity between units, and the application of advanced process control strategies to improve process continuity. To achieve continuous manufacturing of TCM, the corresponding key technologies, such as material property characterization, process modeling and simulation, process analysis technology, and system integration, were analyzed from the process and equipment, respectively. It was proposed that the continuous manufacturing equipment system should have the characteristics of high speed, high response, and high reliability, "three high(H~3)" for short. Considering the characteristics and current situation of TCM manufacturing, based on the two dimensions of product quality control and production efficiency, a maturity assessment model for continuous manufacturing of TCM, consisting of operation continuity, equipment continuity, process continuity, and quality control continuity, was proposed to provide references for the application of continuous manufacturing technology for TCM. The implementation of continuous manufacturing or the application of key continuous manufacturing technologies in TCM can help to systematically integrate advanced pharmaceutical technology elements and promote the uniformity of TCM quality and the improvement of production efficiency.
Medicine, Chinese Traditional ; Reproducibility of Results ; China ; Quality Control ; Pharmaceutical Preparations

Transplantation-associated thrombotic microangiopathy (TA-TMA) is one of the serious complications mostly occurring within 100 days after hematopoietic stem cell transplantation (HSCT). Risk factors of TA-TMA include genetic predispositions, GVHD, and infections. The pathophysiological mechanisms of TA-TMA start with endothelial injury caused by complement activation, which leads to microvascular thrombosis, and microvascular hemolysis, ultimately resulting in multi-organ dysfunction. In recent years, the development of complement inhibitors has markedly improved the prognosis of TA-TMA patients. This review will give an update on risk factors, clinical manifestations, diagnosis, and treatment of TA-TMA, so as to provide references for clinical practice.
Humans ; Thrombotic Microangiopathies/therapy* ; Prognosis ; Thrombosis/etiology* ; Risk Factors ; Hematopoietic Stem Cell Transplantation/adverse effects*