Early cartilage lesion and 5-year incident joint surgery in knee osteoarthritis patients: a retrospective cohort study.

OBJECTIVE: to investigate the association between cartilage lesion-related features observed in knee osteoarthritis (OA) patients' first MRI examination and incident knee surgery within 5 years. Additionally, to assess the predictive value of these features for the incident knee surgery. METHODS: We identified patients diagnosed with knee OA and treated at our institution between January 2015 and January 2018, and retrieved their baseline clinical data and first MRI examination films from the information system. Next, we proceeded to determine joint space narrowing grade, cartilage lesion size grade, cartilage full-thickness loss grade and cartilage lesion sum score for the medial and lateral compartments, respectively. Generalized linear regression models examined the association of these features with 5-year incident knee surgery. Positive and negative predictive values (PPVs and NPVs) were determined referring to 5-year incident knee surgery. RESULTS: Totally, 878 participants (knees) were found eligible to form the study population. Within the 5 years, surgery was performed on 61 knees. None of the cartilage-related features had been found significantly associated with incident surgery. The results were similar for medial and lateral compartments. The PPVs were low for all the features. CONCLUSIONS: Among symptomatic clinically diagnosed OA knees, cartilage lesions observed in the first MRI examinations were not found to be associated with the occurrence of joint surgery within a 5-year period. All these cartilage-related features appear to have no additional value in predicting 5-year incident joint surgery.

Synthesis and anti-tumor activity evaluation of 1H-pyrrolo[2,3-b]pyridine-2-carboxamide derivatives with phenyl sulfonamide groups as potent RSK2 inhibitors.

Ribosome S6 Protein Kinase 2 (RSK2) is involved in many signal pathways such as cell growth, proliferation, survival and migration in tumors. Also, RSK2 can phosphorylate YB-1, which induces the expression of tumor initiating cells, leading to poor prognosis of triple negative breast cancer. Herein, phenyl sulfonamide was introduced to a series of 1H-pyrrolo[2,3-b]pyridine-2-carboxamide derivatives to obtain novel RSK2 inhibitors which were evaluated RSK2 inhibitory activity and proliferation inhibitory activity against MDA-MB-468. The newly introduced sulfonamide group was observed to form a hydrogen bond with target residue LEU-74 which played crucial role in activity. The results showed that most of compounds exhibited RSK2 enzyme inhibitory with IC50 up to 1.7 nM. Compound B1 exhibited the strongest MDA-MB-468 cell anti-proliferation activity (IC50 = 0.13 µM). The in vivo tumor growth inhibitory activities were evaluated with compounds B1-B3 in MDA-MB-468 xenograft model which gave up to 54.6% of TGI.

Implications of altered sirtuins in metabolic regulation and oral cancer.

Sirtuins (SIRTs 1-7) are a group of histone deacetylase enzymes with a wide range of enzyme activities that target a range of cellular proteins in the nucleus, cytoplasm, and mitochondria for posttranslational modifications by acetylation (SIRT1, 2, 3, and 5) or ADP ribosylation (SIRT4, 6, and 7). A variety of cellular functions, including mitochondrial functions and functions in energy homeostasis, metabolism, cancer, longevity and ageing, are regulated by sirtuins. Compromised sirtuin functions and/or alterations in the expression levels of sirtuins may lead to several pathological conditions and contribute significantly to alterations in metabolic phenotypes as well as oral carcinogenesis. Here, we describe the basic characteristics of seven mammalian sirtuins. This review also emphasizes the key molecular mechanisms of sirtuins in metabolic regulation and discusses the possible relationships of sirtuins with oral cancers. This review will provide novel insight into new therapeutic approaches targeting sirtuins that may potentially lead to effective strategies for combating oral malignancies.

Synthesis and in vitro biological evaluation of 3-ethyl-1,5-naphthyridin-2(1H)-one derivatives as potent PARP-1 selective inhibitors and PARP-1 DNA trappers.

Inhibition of poly (ADP-ribose) polymerase (PARP) has been applied with great success in the clinical treatment of homologous recombination-deficient malignancy. Recent study demonstrated that not only PARP-1 inhibition but also DNA trapping contributes to the efficacy in BRCA mutant tumors and the toxicities results from the poor selectivity of PARP-1 over PARP-2 as well as their DNA trapping. Herein, a series of 3-ethyl-1,5-naphthyridin-2(1H)-one derivatives (7a-7l, 8a-8n) were synthesized and identified as PARP-1 selective inhibitors and PARP-1 DNA trappers. Among them, compound 8m was found to be highly potent and selective. It inhibited PARP-1 activity and BRCA mutant DLD-1 cell activity with IC50 values of 0.49 nM and 4.82 nM, and the in vitro DNA trapping efficacy of compound 8m was 1.85 nM. Compared with AZD5305, compound 8m significantly improved the selectivity of PARP-1 over PARP-2 as well. Compound 8m was>1000-fold selective for PARP-1 DNA trapping over PARP-2.

Integrated Analysis of Multiple Microarray Studies to Identify Novel Gene Signatures in Ulcerative Colitis.

Background: Ulcerative colitis (UC) is a chronic, complicated, inflammatory disease with an increasing incidence and prevalence worldwide. However, the intrinsic molecular mechanisms underlying the pathogenesis of UC have not yet been fully elucidated. Methods: All UC datasets published in the GEO database were analyzed and summarized. Subsequently, the robust rank aggregation (RRA) method was used to identify differentially expressed genes (DEGs) between UC patients and controls. Gene functional annotation and PPI network analysis were performed to illustrate the potential functions of the DEGs. Some important functional modules from the protein-protein interaction (PPI) network were identified by molecular complex detection (MCODE), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG), and analyses were performed. The results of CytoHubba, a plug for integrated algorithm for biomolecular interaction networks combined with RRA analysis, were used to identify the hub genes. Finally, a mouse model of UC was established by dextran sulfate sodium salt (DSS) solution to verify the expression of hub genes. Results: A total of 6 datasets met the inclusion criteria (GSE38713, GSE59071, GSE73661, GSE75214, GSE87466, GSE92415). The RRA integrated analysis revealed 208 significant DEGs (132 upregulated genes and 76 downregulated genes). After constructing the PPI network by MCODE plug, modules with the top three scores were listed. The CytoHubba app and RRA identified six hub genes: LCN2, CXCL1, MMP3, IDO1, MMP1, and S100A8. We found through enrichment analysis that these functional modules and hub genes were mainly related to cytokine secretion, immune response, and cancer progression. With the mouse model, we found that the expression of all six hub genes in the UC group was higher than that in the control group (P < 0.05). Conclusion: The hub genes analyzed by the RRA method are highly reliable. These findings improve the understanding of the molecular mechanisms in UC pathogenesis.

Feasibility of totally laparoscopic gastrectomy without prophylactic drains in gastric cancer patients.

BACKGROUND: Prophylactic drains have been used to remove intraperitoneal collections and detect complications early in open surgery. In the last decades, minimally invasive gastric cancer surgery has been performed worldwide. However, reports on routine prophylactic abdominal drainage after totally laparoscopic distal gastrectomy are few. AIM: To evaluate the feasibility performing totally laparoscopic distal gastrectomy without prophylactic drains in selected patients. METHODS: Data of patients with distal gastric cancer who underwent totally laparoscopic distal gastrectomy with and without prophylactic drainage at China National Cancer Center/Cancer Hospital from February 2018 to August 2019 were reviewed. The outcomes between patients with and without prophylactic drainage were compared. RESULTS: A total of 457 patients who underwent surgery for gastric cancer were identified. Of these, 125 patients who underwent totally laparoscopic distal gastrectomy were included. After propensity score matching, data of 42 pairs were extracted. The incidence of concurrent illness was higher in the drain group (42.9% vs 31.0%, P = 0.258). The overall postoperative complication rates were 19.5% and 10.6% in the drain (n = 76) and no-drain groups (n = 49), respectively; there were no significant differences between the two groups (P > 0.05). The difference between the two groups based on the need for percutaneous catheter drainage was also not significant (9.8% vs 6.4%, P = 0.700). However, patients with a larger body mass index (≥ 29 kg/m2) were prone to postoperative complications (P = 0.042). In addition, the number of days from surgery until the first flatus (4.33 ± 1.24 d vs 3.57 ± 1.85 d, P = 0.029) was greater in the drain group. CONCLUSION: Omitting prophylactic drainage may reduce surgery time and result in faster recovery. Routine prophylactic drains are not necessary in selected patients. A prophylactic drain may be useful in high-risk patients.

Survival outcomes and prognostic indicators for gastric cancer patients with positive peritoneal wash cytology but no peritoneal metastasis after radical gastrectomy.

BACKGROUND: Positive peritoneal wash cytology with no peritoneal metastasis (CY1P0) is a special type of distant gastric cancer metastasis, which describes a patient with positive peritoneal lavage cytology, but no definitive peritoneal metastasis, and there are no widely accepted treatment guidelines. We enrolled 48 primary CY1P0 gastric cancer patients treated by radical gastrectomy in this study. Our study illustrated the efficacy of radical gastrectomy for CY1P0 gastric cancer patients, and suggested that the pathological N factor and vascular invasion were significant independent risk factors for overall survival (OS). AIM: To assess the survival of CY1P0 gastric cancer patient post-radical gastrectomy, and to identify factors associated with long-term prognosis. METHODS: Our study included 48 patients with primary CY1P0 gastric cancer who had radical gastrectomies at the Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China between 2013 and 2018. R0 resection was achieved in all 48 patients. Twelve patients received neoadjuvant chemotherapy. Thirty patients received adjuvant chemotherapy and four received adjuvant chemoradiotherapy. OS statistics were available for 48 patients. Follow-up continued through March 2020. Univariate and multivariate analyses were performed using a Cox proportional hazards model to identify prognostic factors. RESULTS: Median OS was 22.0 mo (95% confidence interval: 13.366-30.634 mo) post-surgery. Univariate analyses demonstrated that tumor site (P = 0.021), pathological N factor (P = 0.001), pathological T factor (P = 0.028), vascular invasion (P = 0.046), and the level of CA199 prior to initiating therapy (P = 0.002) were significant risk factors for OS. Multivariate analyses demonstrated that pathological N factor (P = 0.001) and vascular invasion (P = 0.031) were significant independent risk factors for OS. CONCLUSION: This study suggested that radical gastrectomy may be efficient for CY1P0 gastric cancer patient post-radical gastrectomy and the pathological N factor and vascular invasion are significant independent risk factors for OS.

[Clinical effect of sirolimus in treatment of blue rubber bleb nevus syndrome in children: a report of 2 cases and literature review].

To study the clinical effect of oral sirolimus in the treatment of children with blue rubber bleb nevus syndrome (BRBNS) in the gastrointestinal tract, a retrospective analysis was performed on the clinical data and follow-up results of two children with BRBNS treated by sirolimus. The two children with BRBNS had gastrointestinal bleeding and anemia and were treated with sirolimus at a dose of 1 mg/day as part of treatment. The plasma concentration of the drug was maintained between 2.5-12.0 ng/mL. The children showed disappearance of gastrointestinal bleeding and improvements in anemia and coagulation function, and blood transfusion could be stopped during treatment, with no obvious adverse drug reactions. PubMed, Wanfang Data, and CNKI were searched for related articles on sirolimus in the treatment of BRBNS. A total of 26 cases of children with BRBNS, aged 0-18 years, were obtained. With the addition of the 2 cases in this study, sirolimus treatment achieved a satisfactory clinical effect in all 28 cases. Sirolimus may be effective and safe in the treatment of children with BRBNS, and further prospective studies are needed to evaluate the long-term efficacy of this drug.

Design, synthesis and biological activity evaluation of novel 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as potent transforming growth factor-ß (TGF-ß) type I receptor inhibitors.

TGF-ß type I receptor (also known as activin-like kinase 5 or ALK5) plays a critical role in the progression of fibrotic diseases and tumor invasiveness and metastasis, as well. The development of small inhibitors targeting ALK5 has been validated as a potential therapeutic strategy for fibrotic diseases and cancer. Here, we developed various 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as ALK5 inhibitors. The optimization led to identification of potent and selective ALK5 inhibitors 12r. The compound 12r exhibited strong inhibitory activity both in vitro and in vivo, and pharmacokinetics study showed an oral bioavailability of 57.6%. Thus, compound 12r may provide as new therapeutic option as ALK5 TGF-ßR1 inhibitor.

[Study on diagnosis of atypical cerebral cysticercosis].

OBJECTIVE: To analyze the characteristics of the results of serum immunological tests and brain CT image examinations of atypical cerebral cysticercosis patients, so as to provide the reference for improving the diagnosis of the disease. METHODS: Totally 446 suspected cerebral cysticercosis patients were chosen as the study objects, all of them were given experimental treatment with praziquantel, and then the patients with atypical cerebral cysticercosis were diagnosed according to the treatment effect and review results of brain CT or MRI. Meanwhile, all the 446 patients were tested for serum specific IgG and IgG4 antibodies and cysticercus circulating antigen (CAg) by ELISA, McAb ELISA and PEG-ELISA respectively, and the IHA test was also performed. All the patients received the brain CT examinations. The test results were analyzed statistically and the test performances of the methods above-mentioned were calculated. RESULTS: Among the 446 suspected cerebral cysticercosis patients, after the praziquantel treatment, there were 315 patients whose symptoms were alleviated, and they were diagnosed as atypical cerebral cysticercosis. Among the 446 suspected cerebral cysticercosis patients, the positive rates of specific IgG and IgG4 antibodies, and CAg were 15.47%, 15.02%, and 11.21% respectively, and the positive rate of IHA was 28.47% (χ2 = 52.45, P ＜ 0.01). The brain CT examinations showed that there were 79.14% (353/446) of patients with suspected cysticercus foci. The sensitivities of ELISA, McAb-ELISA, PEG-ELISA, IHA test and brain CT examination (suspected cysticercus foci) for the diagnosis of atypical cerebral cysticercosis were 15.36%-96.82%, the specificities were 63.36%-99.24%, the positive predictive values were 86.40%-98.52%, the negative predictive values were 32.83%-98.25%, the positive likelihood ratios were 2.64-27.86, the negative likelihood ratios were 0.05-0.81, and the OR values were 7.16-52.80. The consolidation of the five tests above-mentioned showed the OR value was 108.00, which was 2 times of the OR value of CT examination. CONCLUSIONS: Atypical cerebral cysticercosis is definitely diagnosed mainly by means of evaluating the effect of the diagnostic therapy (anti-cysticercus), and the serum immunological examinations and brain CT examination also have important reference values.

Proto-oncogene c-erbB2 initiates rat primordial follicle growth via PKC and MAPK pathways.

BACKGROUND: c-erbB2, a proto-oncogene coding epidermal growth factor receptor-like receptor, also as a chemosensitivity/prognosis marker for gynecologic cancer, may be involved in initiation of growth of rat primordial follicles. The aim of the present study is to investigate the role and signal pathway of c-erbB2 in onset of rat primordial follicle development. METHODS: The expression of c-erbB2 mRNA and protein in neonatal ovaries cultured 4 and 8 days with/without epidermal growth factor (EGF) were examined by in situ hybridization, RT-PCR and western blot. The function of c-erbB2 in the primordial folliculogenesis was abolished by small interfering RNA transfection. Furthermore, MAPK inhibitor PD98059 and PKC inhibitor calphostin were used to explore the possible signaling pathway of c-erbB2 in primordial folliculogenesis. RESULTS: The results showed that c-erbB2 mRNA was expressed in ooplasm and the expression of c-erbB2 decreased after transfection with c-erbB2 siRNA. Treatment with EGF at 50 ng/ml significantly increased c-erbB2 expression and primary and secondary follicle formation in ovaries. However, this augmenting effect was remarkably inhibited by c-erbB2 siRNA transfection. Furthermore, folliculogenesis offset was blocked by calphostin (5 x 10(-4) mmol/L) and PD98059 (5 x 10(-2) mmol/L), but both did not down-regulate c-erbB2 expression. In contrast, the expressions of p-ERK and p-PKC were decreased obviously by c-erbB2 siRNA transfection. CONCLUSIONS: c-erbB2 initiates rat primordial follicle growth via PKC and MAPK pathways, suggesting an important role of c-erbB2 in rat primordial follicle initiation and development.

Videothoracoscopic drainage for esophageal perforation with mediastinitis in children.

BACKGROUND: Esophageal perforation remains a devastating event that is difficult to diagnose and manage. The overall mortality associated with esophageal perforation can approach 20%, and delay in treatment of more than 24 hours after perforation can result in a doubling of mortality. The treatment option for esophageal perforation with mediastinitis is not very clear and still controversial. METHODS: Between April 2000 and March 2004, 6 males and 2 females, with ages ranging from 2 to 6 years (mean, 3.8 years), underwent videothoracoscopic drainage for esophageal perforation with mediastinitis. RESULTS: The mean hospital length of stay for patients in our series was 34.1 days (range, 14-47 days). There was no perioperative mortality. All patients were discharged from hospital without major sequelae. CONCLUSIONS: Minimally invasive videothoracoscopic drainage is a feasible and effective method for esophageal perforation with mediastinitis in children.