OBJECTIVE: To investigate the clinical characteristics, treatment and prognosis of adult AML patients with NUP98::HOXA9 fusion gene. METHODS: From May 2017 to October 2023， among 2 113 AML patients who visited the Hematology Department of our hospital, patients with NUP98 rearrangements were screened. The clinical characteristics, chromosome karyotypes, immunophenotypes, gene mutations, treatment efficacy and prognosis of the patients with NUP98::HOXA9 positive were analyzed. RESULTS: Among the 2 113 AML patients, there were 18 cases with NUP98 rearrangement, including 14 NUP98::HOXA9 positive cases, with a detection rate of 0.66% (14/2 113). The median age of the NUP98::HOXA9 positive patients was 42.5 (23-64) years old. The most common chromosome karyotype was t(7; 11)(p15; p15). The immunophenotypes of all patients expressed CD13, CD33, CD117 and CD38, and most patients expressed CD34 and cMPO, while only a few expressed HLA-DR. Second-generation sequencing (NGS) was performed to detect genetic mutations associated with leukemia in all 14 patients, and the genes exhibiting a high frequency of mutation were WT1 (10/14), TET2 (7/14), and FLT3-ITD (6/14). Additionally, mutations were also observed in KRAS/NRAS, IDH1, and KIT. Of the 13 patients who received treatment, 9 achieved complete remission (CR), and all 3 patients who received azacytidine(AZA)+ venetoclax (VEN) regimen achieved CR after the first course of treatment. Within this cohort, 6 patients were classified as relapsed/refractory (6/13). 4 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), of which two achieved long-term survival. The median follow-up time was 12 (2.1-65.0) months, while the median overall survival (OS) and relapse-free survival (RFS) were recorded as 11.4 months and 9.6 months, respectively. CONCLUSION The most common type of NUP98 rearrangement in adults AML patients is NUP98::HOXA9 , which is often accompanied by somatic mutations in WT1, TET2, and FLT3-ITD. These patients are prone to relapse, have short survival time, and generally face poor prognoses. Hopefully, utilization of the AZA+VEN regimen is anticipated to enhance the rate of induced remission in the patients, and some patients may prolong their survival through allo-HSCT. However, more effective treatment methods are still needed to improve the overall prognosis of these patients.
Humans ; Adult ; Leukemia, Myeloid, Acute/genetics* ; Middle Aged ; Prognosis ; Nuclear Pore Complex Proteins/genetics* ; Oncogene Proteins, Fusion/genetics* ; Mutation ; Male ; Female ; Young Adult ; Homeodomain Proteins/genetics*

The purpose of this study was to investigate the regulatory effects of biofilm associated non-coding small RNA(sRNA)00085 on the survival and environmental fitness of Listeria monocytogenes.Homologous recombination technology was used to construct a deletion mutant strain(△sRNA 00085)and a complementary strain(C △sRNA 00085)of the sRNA00085 target gene.The differences in biological characteristics were compared among the standard strain,△sRNA 00085,and C△sRNA 00085.The deletion of sRNA00085 led to a significant decrease in biofilm formation capacity and sensitivity to several antibiotics,including penicillin,piperacillin,doxycycline,tetracycline,vancomycin,and cotrimoxazole.However,only the minimum inhibitory concentration(MIC)of tetracycline exhibited a significant decrease in △sRNA00085.Meanwhile,the decreased biofilm formation and antibiotic resistance of the sRNA00085 mutant were restored in the C△sRNA00085 strain.Furthermore,we investigated the transcription levels of tetracycline resistance-related genes in L.monocytogenes.Down-regu-lated transcription of the tetS gene but no significant difference in transcription of the tetA gene were observed in △sRNA 00085 compared with the standard strain and C△sRNA00085.Moreover,the elimination of sRNA00085 did not affect bacterial growth ability or sensitivity to disinfectants.These findings highlight that sRNA00085 plays an important role in the environ-mental adaptability of L.monocytogenes by affecting bacterial biofilm formation and resistance.

To explore the mechanism by which vinegar-processed Euphorbiae Pekinensis Radix regulates gut microbiota and reduces intestinal toxicity, this study aimed to identify key microbial communities related to vinegar-induced detoxification and verify their functions. Using a derivatization method, the study measured the content of short-chain fatty acids(SCFAs) in feces before and after vinegar-processing of Euphorbiae Pekinensis Radix. Combined with the results of previous gut microbiota sequencing, correlation analysis was used to identify key microbial communities related to SCFAs content. Through single-bacterium transplantation experiments, the role of key microbial communities in regulating SCFAs metabolism and alleviating the intestinal toxicity of Euphorbiae Pekinensis Radix was clarified. Fecal extracts were then added to a co-culture system of Caco-2 and RAW264.7 cells, and toxicity differences were evaluated using intestinal tight junction proteins and inflammatory factors as indicators. Additionally, the application of a SCFAs receptor blocker helped confirm the role of SCFAs in reducing intestinal toxicity during vinegar-processing of Euphorbiae Pekinensis Radix. The results of this study indicated that vinegar-processing of Euphorbiae Pekinensis Radix improved the decline in SCFAs content caused by the raw material. Correlation analysis revealed that Bifidobacterium was positively correlated with the levels of acetic acid, propionic acid, isobutyric acid, n-butyric acid, isovaleric acid, and n-valeric acid. RESULTS:: from single-bacterium transplantation experiments demonstrated that Bifidobacterium could mitigate the reduction in SCFAs content induced by raw Euphorbiae Pekinensis Radix, enhance the expression of tight junction proteins, and reduce intestinal inflammation. Similarly, cell experiment results confirmed that fecal extracts from Bifidobacterium-transplanted mice alleviated inflammation and increased the expression of tight junction proteins in intestinal epithelial cells. The use of the free fatty acid receptor-2 inhibitor GLPG0974 verified that this improvement effect was related to the SCFAs pathway. This study demonstrates that Bifidobacterium is the key microbial community responsible for reducing intestinal toxicity in vinegar-processed Euphorbiae Pekinensis Radix. Vinegar-processing increases the abundance of Bifidobacterium, elevates the intestinal SCFAs content, inhibits intestinal inflammation, and enhances the expression of tight junction proteins, thereby improving the intestinal toxicity of Euphorbiae Pekinensis Radix.
Animals ; Mice ; Humans ; Acetic Acid/chemistry* ; Gastrointestinal Microbiome/drug effects* ; Fatty Acids, Volatile/metabolism* ; Bifidobacterium/genetics* ; Caco-2 Cells ; Intestines/microbiology* ; Drugs, Chinese Herbal/chemistry* ; Euphorbia/toxicity* ; RAW 264.7 Cells ; Male ; Feces/chemistry* ; Intestinal Mucosa/drug effects*

In the research on cancer theranostics, most environment-sensitive drug delivery systems can only achieve unidirectional and irreversible responsive changes under pathological conditions, thereby improving the targeting effect and drug release performance of the delivery system. However, such irreversible changes pose potential safety hazards when the dynamically distributed delivery system returns to the blood circulation or transports to the normal physiological environment. Intelligent reversible drug delivery systems can respond to normal physiological and pathological microenvironments to achieve bidirectional and reversible structural changes. This feature will help to precisely control the drug release of the delivery system, prolong the blood circulation time, improve the targeting efficiency, and avoid the potential safety hazards of the irreversible drug delivery system. In this review, we describe the research progress of intelligent reversible drug delivery system from two main aspects: controlled drug release and prolonged blood circulation time/enhanced cellular internalization of drug.

Humans ; Factor XIII/genetics* ; Factor XIII Deficiency/genetics* ; Mutation ; Pedigree

This study investigated the effect of eleutheroside B on apoptosis and autophagy of lung cancer A549 and H460 cells and its molecular mechanism. MTT assay was used to detect the cytotoxicity of eleutheroside B at 5, 10, 15, 20, 25, 30, 35, 40, and 45 mmol·L~(-1) on lung cancer cells. Trypan blue exclusion assay was used to detect the effect of eleutheroside B on the survival rate of lung cancer A549 and H460 cells at different time. Colony formation assay was used to detect the effect of eleutheroside B on the proliferation of lung cancer A549 and H460 cells. AO/EB fluorescence double staining and Hoechst 33342 fluorescence staining were used to detect the effect of eleutheroside B on apoptosis of lung cancer A549 and H460 cells, and Western blot was used to detect apoptosis-related proteins to explore the apoptosis-related molecular mechanism. AO fluorescence staining and Western blot were used to detect the expression of autophagic vesicles and autophagy-related proteins P62 and LC3. The results showed that compared with the control group, eleutheroside B inhibited the growth of lung cancer A549 and H460 cells in a concentration-dependent manner. The optimal effect time of eleutheroside B on lung cancer A549 and H460 cells was 24 h, and the optimal concentrations were 28.64 and 22.16 mmol·L~(-1), respectively. Eleutheroside B could inhibit the colony formation of A549 and H460 cells. Compared with the control group, eleutheroside B could promote the formation of apoptotic bodies and induce cell apoptosis, as well as induce the expression of mitochondrial pathway-related proteins. Under the effect of eleutheroside B, the acidic autophagy vacuole in lung cancer cells increased, LC3Ⅱ expression increased, P62 protein expression decreased, and PI3K, p-Akt, and p-mTOR protein expression decreased in the PI3K/Akt/mTOR pathway. Studies have shown that eleutheroside B can inhibit the growth of lung cancer cells, reduce colony formation, induce apoptosis of lung cancer cells through mitochondrial pathway, and induce autophagy. The mechanism may be related to the PI3K/Akt/mTOR pathway.
Humans ; Lung Neoplasms/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism* ; Apoptosis ; Apoptosis Regulatory Proteins ; Autophagy ; Cell Proliferation ; Cell Line, Tumor ; Glucosides ; Phenylpropionates

This study aimed to explore the effects and mechanisms of total flavones of Abelmoschus manihot(TFA), the extracts from traditional Chinese medicine indicated for kidney diseases, on insulin resistance(IR) and podocyte epithelial-mesenchymal transition(EMT) in diabetic kidney disease(DKD), and further to reveal the scientific connotation. Thirty-two rats were randomly divided into a normal group, a model group, a TFA group, and a rosiglitazone(ROS) group. The modified DKD model was induced in rats by methods including high-fat diet feeding, unilateral nephrectomy, and streptozotocin(STZ) intraperitoneal injection. After modeling, the rats in the four groups were given double-distilled water, TFA suspension, and ROS suspension correspondingly by gavage every day. At the end of the 8th week of drug administration, all rats were sacrificed, and the samples of urine, blood, and kidney tissues were collected. The parameters and indicators related to IR and podocyte EMT in the DKD model rats were examined and observed, including the general condition, body weight(BW) and kidney weight(KW), the biochemical parameters and IR indicators, the protein expression levels of the key signaling molecules and structural molecules of slit diaphragm in the renal insulin receptor substrate(IRS) 1/phosphatidylinositol 3-kinase(PI3K)/serine-threonine kinase(Akt) pathway, foot process form and glomerular basement membrane(GBM) thickness, the expression of the marked molecules and structural molecules of slit diaphragm in podocyte EMT, and glomerular histomorphological characteristics. The results showed that for the DKD model rats, both TFA and ROS could improve the general condition, some biochemical parameters, renal appearance, and KW. The ameliorative effects of TFA and ROS were equivalent on BW, urinary albumin(UAlb)/urinary creatinine(UCr), serum creatinine(Scr), triglyceride(TG), and KW. Secondly, they could both improve IR indicators, and ROS was superior to TFA in improving fast insulin(FIN) and homeostasis model assessment of insulin resistance(HOMA-IR). Thirdly, they could both improve the protein expression levels of the key signaling molecules in the IRS1/PI3K/Akt pathway and glomerulosclerosis in varying degrees, and their ameliorative effects were similar. Finally, both could improve podocyte injury and EMT, and TFA was superior to ROS. In conclusion, this study suggested that podocyte EMT and glomerulosclerosis could be induced by IR and the decreased activation of the IRS1/PI3K/Akt pathway in the kidney in DKD. Similar to ROS, the effects of TFA in inhibiting podocyte EMT in DKD were related to inducing the activation of the IRS1/PI3K/Akt pathway and improving IR, which could be one of the scientific connotations of TFA against DKD. This study provides preliminary pharmacological evidence for the development and application of TFA in the field of diabetic complications.
Rats ; Animals ; Diabetic Nephropathies/drug therapy* ; Proto-Oncogene Proteins c-akt/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Abelmoschus/chemistry* ; Podocytes ; Rats, Sprague-Dawley ; Epithelial-Mesenchymal Transition ; Flavones/pharmacology* ; Insulin Resistance ; Reactive Oxygen Species ; Diabetes Mellitus