Targeting cyclin-dependent kinase 9 in cancer therapy.

Cyclin-dependent kinase (CDK) 9 associates mainly with cyclin T1 and forms the positive transcription elongation factor b (p-TEFb) complex responsible for transcriptional regulation. It has been shown that CDK9 modulates the expression and activity of oncogenes, such as MYC and murine double minute 4 (MDM4), and it also plays an important role in development and/or maintenance of the malignant cell phenotype. Malfunction of CDK9 is frequently observed in numerous cancers. Recent studies have highlighted the function of CDK9 through a variety of mechanisms in cancers, including the formation of new complexes and epigenetic alterations. Due to the importance of CDK9 activation in cancer cells, CDK9 inhibitors have emerged as promising candidates for cancer therapy. Natural product-derived and chemically synthesized CDK9 inhibitors are being examined in preclinical and clinical research. In this review, we summarize the current knowledge on the role of CDK9 in transcriptional regulation, epigenetic regulation, and different cellular factor interactions, focusing on new advances. We show the importance of CDK9 in mediating tumorigenesis and tumor progression. Then, we provide an overview of some CDK9 inhibitors supported by multiple oncologic preclinical and clinical investigations. Finally, we discuss the perspective and challenge of CDK9 modulation in cancer.

Screening of genes involved in epithelial-mesenchymal transition and differential expression of complement-related genes induced by PAX2 in renal tubules.

AIM: The aim of the present study was to screen and verify downstream genes involved in the epithelial mesenchymal transition (EMT) induced by paired box 2 (PAX2) in NRK-52E cells. METHODS: NRK-52E cells were transfected with lentivirus carrying PAX2 gene or no-load virus respectively. Total RNA was isolated 72 h after transfection from PAX2-overexpressing cells and control cells. Isolated RNA was then hybridized with the Rat OneArray Plus expression profile chip. The chips were examined by Agilent 0.1 XDR to screen for differentially expressed genes, which were further analyzed to investigate complement-related genes as genes of interest. RESULTS: In NRK-52E cells, PAX2 overexpression promoted EMT followed by upregulation of 298 genes and downregulation of 293 genes. KEGG analysis indicated the differential expression of genes related to cytokines and their receptors, extracellular matrix (ECM), MAPKs, local adhesion, cancer, the complement cascade, and coagulation. Gene oncology analysis screened out genes related to molecular functions (e.g., hydrolase activity, phospholipase activity, components of the ECM) and biological processes (e.g., cell development, signal transduction, phylogeny), and cell components (e.g., cytoplasm, cell membrane, and ECM). Analysis of the complement system revealed upregulation of C3 and downregulation of CD55 and complement regulator factor H (CFH). CONCLUSION: PAX2 overexpression upregulates EMT in vitro and may regulate C3, CD55, and CFH.

Giant myxofibrosarcoma of the esophagus treated by endoscopic submucosal dissection: A case report.

BACKGROUND: Myxofibrosarcoma (MFS) is a fibroblast-derived sarcoma that mainly occurs in subcutaneous tissue. MFS rarely occurs in the gastrointestinal tract, especially in the esophagus. CASE SUMMARY: A 79-year-old male patient was admitted to our hospital for dysphagia for a week. Computed tomography and electronic gastroscopy showed that a giant mass was located 30 cm from the incisor and extended to the cardia. There was incomplete esophageal stenosis. Endoscopic pathology showed spindle cell lesions, which were considered inflammatory myofibroblast like hyperplasia. Considering the strong demands of the patient and his family, and the fact that most inflammatory myofibroblast tumors are benign, we decided to perform endoscopic submucosal dissection (ESD) even if the tumor size was giant (9.0 cm × 3.0 cm). Postoperative pathological examination resulted in a final diagnosis of MFS. MFS rarely occurs in the gastrointestinal tract, especially in the esophagus. Surgical resection and local adjuvant radiotherapy are the first choices to improve the prognosis. This case report firstly described the ESD for esophageal giant MFS. It suggests that ESD may be an alternative treatment for primary esophageal MFS. CONCLUSION: This case report for the first time describe the successful treatment of a giant esophageal MFS by ESD, suggesting that ESD may be an alternative treatment for primary esophageal MFS, especially in elderly high-risk patients with obvious dysphagia symptoms.

Risk factors for renal outcomes in children with antineutrophil cytoplasmic antibody-associated vasculitis: a nationwide retrospective study in China.

BACKGROUND: Pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a life-threatening systemic vasculitis featured by liability to renal involvement. However, there are few studies on the risk factors and predictive models for renal outcomes of AAV in children. METHODS: Data from 179 AAV children in multiple centers between January 2012 and March 2020 were collected retrospectively. The risk factors and predictive model of end-stage renal disease (ESRD) in AAV were explored. RESULTS: Renal involvement was the most typical manifestation (95.5%), and the crescent was the predominant pathological lesion (84.9%). The estimated glomerular filtration rate (eGFR) was evaluated in 114 patients, of whom 59.6% developed ESRD, and the median time to ESRD was 3.20 months. The eGFR [P = 0.006, odds ratio (OR) = 0.955, 95% confidence interval (CI) = 0.924-0.987] and the percentages of global glomerulosclerosis (pGGS; P = 0.018, OR = 1.060, 95% CI = 1.010-1.112) were independent risk factors for ESRD of renal biopsy. Based on the pGGS and eGFR at renal biopsy, we developed three risk grades of ESRD and one predictive model. The Kaplan‒Meier curve indicated that renal outcomes were significantly different in different risk grades (P < 0.001). Compared with serum creatinine at baseline, the predictive model had higher accuracy (0.86 versus 0.58, P < 0.001) and a lower coefficient of variation (0.07 versus 0.92) in external validation. CONCLUSIONS: Renal involvement is the most common manifestation of pediatric AAV in China, of which more than half deteriorates into ESRD. The predictive model based on eGFR at renal biopsy and the pGGS may be stable and accurate in speculating the risk of ESRD in AAV children. Supplementary file 2 (MP4 18937 KB).

Clinical Analysis of 44 Children with Subacute Necrotizing Lymphadenitis.

Objective: To explore the causes, clinical features, and laboratory examination characteristics of subacute necrotizing lymphadenitis to improve the understanding of this disease, reduce misdiagnosis, and make appropriate diagnoses and treatments. Methods: The clinical data of 44 children with subacute necrotizing lymphadenitis admitted to our hospital from January 2013 to August 2021 were collected. The clinical and laboratory examinations of the disease were systematically analyzed. Results: All 44 cases aged 6-13 years and averaged 10.3 ± 2.1 years, including 32 boys and 12 girls, were diagnosed with histiocytic necrotizing lymphadenitis (HNL) by lymph node biopsy. Forty-two cases had palpable superficial lymph nodes, and two showed abdominal lymph node enlargement in the imaging examination. The symptoms might be accompanied by mild hepatomegaly or splenomegaly, emaciation, night sweats, rashes, and other manifestations. Leukopenia and neutropenia occurred. The pathological features were extensive coagulative necrosis of lymph nodes with reactive hyperplasia of histiocytes as well as positive IHCl CD68. Four cases had a relapse, and the prognosis of the other cases was good. Conclusion: The case with fever and lymph node enlargement of unknown origin and no response to antibiotic treatment should undergo a pathological examination as early as possible for diagnosis and treatment. The disease has a good prognosis in most cases but may recur in a few cases.

Ethyl (Z)-2-(2-fluoro-benzyl-idene)-7-methyl-3-oxo-5-phenyl-3,5-dihydro-2H-thia-zolo[3,2-a]pyrimidine-6-carboxyl-ate.

The title compound, C(23)H(19)FN(2)O(3)S, a fused-pyrimidine derivative, displays dihedral angles between the thia-zole ring and the benzene ring and substituted benzene ring of 7.10 (14) and 3.48 (12)°, respectively. The dihydro-pyrimidine ring adopts a flattened boat conformation. The olefinic double bond is in a Z configuration.

A review of nephrotic syndrome and atopic diseases in children.

Pediatric nephrotic syndrome (NS) is a common and recurrent glomerular disease in childhood. Furthermore, 50-70% of children with NS have increased total IgE in peripheral blood and a variety of clinical manifestations of atopic diseases. Hence, NS has many similarities with atopic diseases. However, no study has revealed a clear link between these two diseases. The present review discusses the correlation between pediatric NS and atopic diseases in children from three aspects: pathogenesis, cytokine change, and treatment. There are similar changes in T cells in terms of pathogenesis, with Th1/Th2 dysfunction and Treg cell function downregulation. Cytokine changes are similar and manifest as an increase in Th2 cytokines, TNF-α and TGF-ß1, and a decrease in IL-10. Glucocorticoids, immunosuppressants and biological agents are used for the treatment of these two diseases. Therefore, it was speculated that NS and atopic diseases may be the same kind of disease, have a similar pathogenesis, and only exhibit different clinical manifestations due to different affected parts of the disease.

Streptococcal pneumonia-associated hemolytic uremic syndrome treated by T-antibody-negative plasma exchange in children: Two case reports.

BACKGROUND: The occurrence of Streptococcus pneumoniae-associated hemolytic uremic syndrome (SP-HUS) is increasing. Thomsen-Friedenreich antigen activation is highly involved in the pathogenesis of SP-HUS, and T-antibody-negative plasma exchange (PE) may be effective in the treatment of severe cases of SP-HUS. CASE SUMMARY: We retrospectively reviewed two pediatric patients with SP-HUS. Both clinical features and laboratory examination results of the children were described. T-antibody-negative PE was performed in both cases. Both children made a full recovery after repeated PE and remained well at a 2 year follow-up. CONCLUSION: Streptococcal pneumonia continues to be an uncommon but important cause of HUS. The successful treatment of the presented cases suggests that T-antibody-negative PE may benefit patients with SP-HUS.

Clinical Correlation Between Overactive Bladder and Allergy in Children.

BACKGROUND: The International Children's Continence Society defines overactive bladder (OAB) as a clinical syndrome characterized by urgency of urination usually accompanied by frequent urination and nocturia symptoms. This study aims to explore the correlation between overactive bladder (OAB) and allergy in children. METHOD: The clinical characteristics of 918 patients diagnosed with OAB from January 2020 to March 2021 were retrospectively analyzed. Risk factors for OAB were analyzed using logistic regression analysis, and the effect of desloratadine in the treatment of OAB was evaluated. RESULTS: The incidence of allergic cough or allergic rhinitis in the mild OAB group was higher than the moderate-severe group. Urodynamics demonstrated that the proportion of patients with a sensitive bladder in the overactive detrusor group was significantly higher than the non-overactive detrusor group. The effective rate of treatment of OAB in patients complicated with allergies and taking desloratadine was 90.14%, which was significantly higher than in patients who were not taking desloratadine, and blood IgE level was a risk factor of ineffective treatment with desloratadine. CONCLUSION: OAB is correlated with allergies in children, and desloratadine can effectively improve OAB symptoms.

[Effects of glutamine on extracellular signal regulated kinase and p38MAPK expression in the kidney in young rats with endotoxemia].

OBJECTIVE: Glutamine has protective effects against renal injuries. This study was designed to explore the possible mechanism underlying the protections by examining the effects of glutamine on extracellular signal regulated kinase (ERK) and p38MAPK expression in the kidney in rats with endotoxemia. METHODS: One hundred and twenty-one 18-day-old Wistar rats were randomly injected with LPS (4 mg/kg; n=55), LPS (4 mg/kg)+glutamine (1 mL/kg) (n=55), or normal saline (control group; n=11). The two LPS groups were subdivided into five groups sacrificed at 2, 4, 6, 24 and 72 hrs after administration (n=11 each). ERK-2 and p38MAPK mRNA and protein expression in the kidney were measured by RT-PCR and immunohistochemistry. RESULTS: Compared to the control group, the mRNA and protein expression of both ERK-2 and p38MAPK in the LPS group significantly increased 2, 4, 6, 24 and 72 hrs after administration (P<0.01), and reached a peak at 6 hrs (P<0.01). In the LPS+glutamine group, the trend of ERK-2 and p38MAPK expression was similar to the LPS group but their expression levels were significantly lower than those in the LPS group at all time points (P<0.05 or 0.01). CONCLUSIONS: Both ERK-2 and p38MAPK expression increased in young rats with LPS-induced endotoxemia. Glutamine alleviates renal injuries possibly by decreasing the expression of both.

Effects of Huaiqihuang Granules Adjuvant Therapy in Children with Primary Nephrotic Syndrome.

OBJECTIVE: This study aims to observe the curative effect of Huaiqihuang Granules adjuvant therapy on primary nephrotic syndrome (PNS). METHODS: A total of 112 children with PNS were randomly divided into three groups, and changes in serum inflammatory cytokines, interleukin, lymphocyte subsets and immunoglobulin were observed. RESULTS: Before treatment, IL-18, TNF-α, CD8+ increased, while IL-10, CD4+, NK cells, IgA, IgG and Foxp3+Treg cells decreased. After Huaiqihuang Granules treatment, IL-18, TNF-α, CD8+ decreased, while IL-10, CD4+, NK cells, IgA, IgG and Foxp3+Treg cells increased. CONCLUSION: Functions of cell immunity and humoral immunity in PNS patients before treatment were suppressed and disordered. Huaiqihuang granules can play a role in immunoregulation, with slight side reactions.

Expression characteristics of KAI1 and vascular endothelial growth factor and their diagnostic value for hepatocellular carcinoma.

BACKGROUND/AIMS: We tried to investigate the expression characteristics of KAI1, a suppressor of wide-spectrum tumor metastasis, and vascular endothelial growth factor (VEGF), the most common angiogenesis factor, and then to analyze their diagnostic value for hepatocellular carcinoma (HCC). METHODS: The protein and mRNA expression levels of KAI1 or VEGF in HCC tissues and in self-controlled para-carcinoma tissues were analyzed by Western blot and real-time polymerase chain reaction, respectively. Serum levels of KAI1 and VEGF in the patients with HCC, benign liver disease or in healthy controls were quantitatively detected by enzyme-linked immunosorbent assay. RESULTS: The expression level of KAI1 was downregulated, while the expression level of VEGF was upregulated in the tissues or serum of the patients with HCC. The expression level of serum KAI1 in HCC patients was correlated with TNM staging, intrahepatic metastasis, lymph node or peritoneal metastasis, and portal vein thrombus. In addition to the factors that were correlated with KAI1 expression, VEGF expression was also closely related to the α-fetoprotein level of the patients. The area under the receiver operating characteristic curve for the diagnosis of HCC was 0.907 for KAI1 and 0.779 for VEGF. The sensitivity of serum KAI1 levels in the diagnosis of HCC was 86.96%; the accuracy was 83.06%, while the sensitivity, the accuracy and the negative predictive value were improved to 91.86%, 84.68%, and 78.79% according to the combined detection of KAI1 and VEGF, respectively. CONCLUSIONS: A combined detection of KAI1 and VEGF may greatly improve the efficiency of diagnosis and form a reliable panel of diagnostic markers for HCC.

Therapeutic potential of EGCG on acute renal damage in a rat model of obstructive nephropathy.

As a major active component in green tea, (-)-epigallocatechin 3-O-gallate (EGCG) has many anti-oxidative activities. This study investigated whether intraperitoneal administration of EGCG was capable of suppressing oxidative stress in rats with unilateral ureteral obstruction (UUO) and probed the potential mechanisms involved. In total, 150 adult male rats were randomly divided into 5 groups (n=30 each): the control group (group N); the unilateral ureteral obstruction (UUO) group (group C), where the unilateral ureter was ligated resulting in an obstructive nephropathy model; and the EGCG group (group T), following unilateral ureteral ligation, rats were intraperitoneally injected with EGCG at a dosage of 2.5 (T1), 5 (T2) and 10 mg/kg/day (T3). Each group of rats was sacrificed 72 h after surgery. We evaluated the effects of EGCG on the reactive oxygen species (ROS), reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione in the renal tissue of rats. Immunohistochemistry and western blot analysis were applied to detect nuclear factor erythoid-derived 2-related factor 2 (Nrf2) and γ-glutamylcysteine synthetase (γ-GCS) protein expression. Real-time PCR was performed to detect the mRNA levels of Nrf2 and γ-GCS. Changes in renal ultrastructure were also observed using electron microscopy. There was no significant difference in GSH, and compared with group N, ROS, GSSG and total GSH levels were much higher in the T groups (p<0.01), while much lower than those of group C (p<0.01). Protein levels of Nrf2 and γ-GCS and the mRNA levels of Nrf2 and γ-GCS notably increased in EGCG-treated rats (all p<0.05). Furthermore, electron microscopy showed that renal ultrastructure was improved in the treatment groups. Our findings suggest that, resulting from suppression of oxidative stress influenced by free radicals, EGCG exerts a protective effect on rats with obstructive nephropathy, and this anti-oxidative effect may be partly induced by activating the Nrf2 signaling pathway.

Synthesis, structure, and bioevaluation of 2,5-bis(arylmethenyl)cyclopentanones.

Curcumin is an excellent lead compound with a variety of bioactivity. Recent articles reported that curcumin's instability and low bioavailability in vivo are mainly due to its easily decomposable beta-diketone moiety. With the aim of bioactive curcumin analogs with better pharmacokinetic property, we present here 11 bis(arylmethenyl)cyclopentanones similar to curcumin and without beta-diketone moiety by reacting relevant arylaldehydes and cyclopentanones. The analogs were structurally determined by 1HNMR and MS spectra, and the crystal structure of 6 was analyzed by X-ray diffraction. Their antibacterial activities in vitro against seven Gram-positive and Gram-negative bacteria were tested, and their inhibition of TNF-alpha and IL-6 secretion in LPS-induced mouse macrophages was investigated using enzyme-linked immunosorbent assay. It was observed that several derivatives displayed higher activity when compared with curcumin, and most of the analogs exhibited activities against the ampicillin-resistant Gram-negative Enterobacter cloacae.