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.

Multi-omics reveals the mechanisms of DEHP driven pulmonary toxicity in ovalbumin-sensitized mice.

The plasticizer di- (2-ethylhexyl) phthalate (DEHP) is considered a risk factor for allergic diseases and has attracted public attention for its adverse effects on health. However, respiratory adverse effects after DEHP exposure in food allergies have rarely been reported. MiRNAs are considered to be key regulators in the complex interrelationships between the host and microbiome and may be a potential factor involved in DEHP-induced pulmonary toxicity. To investigate the adverse effects of DEHP on the lung during sensitization, we established an ovalbumin (OVA)-sensitized mouse model exposed to DEHP and performed 16S rDNA gene sequencing, miRNA sequencing, and correlation analysis. Our results showed that DEHP aggravated the immune disorder in OVA-sensitized mice, which was mainly characterized by an increase in the proportion of Th2 lymphocytes, and further enhanced OVA-induced airway inflammation without promoting pulmonary fibrosis. Compared with the OVA group, DEHP interfered with the lung microbial community, making Proteobacteria the dominant phylum, while Bacteroidetes were significantly reduced. Differentially expressed miRNAs were enriched in the PI3K/AKT pathway, which was closely related to immune function and airway inflammation. The expression of miR-146b-5p was elevated in the DEHP group, which was positively correlated with the proportion of Th2 cells and significantly negatively correlated with the abundance of Bacteroidetes. The results indicate that DEHP may interfere with the expression of miR-146b-5p, affect the composition of the lung microbiota, induce an imbalance in T cells, and lead to immune disorders and airway inflammation. The current study uses multi-omics to reveal the potential link between the plasticizer DEHP and allergic diseases and provides new insights into the ecotoxicology of environmental exposures to DEHP.

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.

Cationic NHC-Phosphine Iridium Complexes: Highly Active Catalysts for Base-Free Hydrogenation of Ketones.

Novel bidentate N-heterocyclic carbene-phosphine iridium complexes have been synthesized and evaluated in the hydrogenation of ketones. Reported catalytic systems require base additives and, if excluded, need elevated temperature or high pressure of hydrogen gas to achieve satisfactory reactivity. The developed catalysts showed extremely high reactivity and good enantioselectivity under base-free and mild conditions. In the presence of 1 mol % catalyst under 1 bar hydrogen pressure at room temperature, hydrogenation was complete in 30 minutes giving up to 96 % ee. Again, this high reactivity was achieved in additive-free conditions. Mechanistic experiments demonstrated that balloon pressure of hydrogen was sufficient to form the activate species by reducing and eliminating the 1,5-cyclooctadiene ligand. The pre-activated catalyst was able to hydrogenate acetophenone with 89 % conversion in 5 min.

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.

[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.

Palladium-Catalyzed Oxidative Synthesis of α-Acetoxylated Enones from Alkynes.

We report a palladium-catalyzed oxidative functionalization of alkynes to generate α-acetoxylated enones in one step. A range of functional groups are well-tolerated in this reaction. Mechanistic studies, including the use of (18) O-labeled DMSO, revealed that the ketone oxygen atom in the product originates from DMSO.

C-C coupling of ketones with methanol catalyzed by a N-heterocyclic carbene-phosphine iridium complex.

An N-heterocyclic carbene-phosphine iridium complex system was found to be a very efficient catalyst for the methylation of ketone via a hydrogen transfer reaction. Mild conditions together with low catalyst loading (1 mol %) were used for a tandem process which involves the dehydrogenation of methanol, C=C bond formation with a ketone, and hydrogenation of the new generated double bond by iridium hydride to give the alkylated product. Using this iridium catalyst system, a number of branched ketones were synthesized with good to excellent conversions and yields.

C-N Coupling of Amides with Alcohols Catalyzed by N-Heterocyclic Carbene-Phosphine Iridium Complexes.

N-Heterocyclic carbene-phosphine iridium complexes (NHC-Ir) were developed/found to be a highly reactive catalyst for N-monoalkylation of amides with alcohols via hydrogen transfer. The reaction produced the desired product in high isolated yields using a wide range of substrates with low catalyst loading and short reaction times.

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.

Highly enantioselective iridium-catalyzed hydrogenation of α,ß-unsaturated esters.

α,ß-Unsaturated esters have been employed as substrates in iridium-catalyzed asymmetric hydrogenation. Full conversions and good to excellent enantioselectivities (up to 99 % ee) were obtained for a broad range of substrates with both aromatic- and aliphatic substituents on the prochiral carbon. The hydrogenated products are highly useful as building blocks in the synthesis of a variety of natural products and pharmaceuticals.

Chiral hetero- and carbocyclic compounds from the asymmetric hydrogenation of cyclic alkenes.

Several types of chiral hetero- and carbocyclic compounds have been synthesized by using the asymmetric hydrogenation of cyclic alkenes. N,P-Ligated iridium catalysts reduced six-membered cyclic alkenes with various substituents and heterofunctionality in good to excellent enantioselectivity, whereas the reduction of five-membered cyclic alkenes was generally less selective, giving modest enantiomeric excesses. The stereoselectivity of the hydrogenation depended more strongly on the substrate structure for the five- rather than the six-membered cyclic alkenes. The major enantiomer formed in the reduction of six-membered alkenes could be predicted from a selectivity model and isomeric alkenes had complementary enantioselectivity, giving opposite optical isomers upon hydrogenation. The utility of the reaction was demonstrated by using it as a key step in the preparation of chiral 1,3-cis-cyclohexane carboxylates.

Effects of endocrine disrupting chemicals in host health: Three-way interactions between environmental exposure, host phenotypic responses, and gut microbiota.

Endocrine disrupting chemicals (EDCs) have gradually become a global health hazard in recent decades. Gut microbiota (GM) provides a crucial interface between the environment and the human body. A triad relationship may exist between EDCs exposure, host phenotypic background, and GM effects. In this review, we attempted to parse out the contribution of GM on the alteration of host phenotypic responses induced by EDCs, suggesting that GM intervention may be used as a therapeutic strategy to limit the expansion of pathogen. These studies can increase the understanding of pathogenic mechanisms, and help to identify the modifiable environmental factors and microbiota characteristics in people with underlying disease susceptibility for prevention and remediation.

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.

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.

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.

Anal swab as a potentially optimal specimen for SARS-CoV-2 detection to evaluate hospital discharge of COVID-19 patients.

Since December 2019, an outbreak of SARS coronavirus 2 (SARS-CoV-2) began in Wuhan, and has rapidly spread worldwide. Previously, discharged patients with coronavirus disease 2019 (COVID-19) patients met the criteria of China's pneumonia diagnosis and treatment program of novel coronavirus infection (trial version 7) for cure of viral infection. Nevertheless, positive detection of SARS-CoV-2 has been found again in several cured COVID-19 patients, leading to conflicts with current criteria. Here, we report clinically cured cases with positive results only in anal swabs, and investigate the clinical value of anal swabs for SARS-CoV-2 detection.

Effects of d-valine on periodontal or peri-implant pathogens: Porphyromonas gingivalis biofilm.

BACKGROUND: When presented with a surface or an interface, bacteria often grow as biofilms in which cells are held together by an extracellular matrix. Biofilm formation on implants is an initiating factor for their failure. Porphyromonas gingivalis is the primary etiologic bacteria of initiation and progression of periodontal disease. This microorganism is also the risk factor of many systemic diseases, such as cardiovascular disease, diabetes, and pulmonary infection. To date, no medication that can remove such biofilm has been accepted for clinical use. D-valine (D-val) can reportedly inhibit the formation of biofilm and/or trigger the scattering of mature biofilm. Accordingly, this study investigated the effects of d-val on single-species P. gingivalis biofilms in vitro. METHODS: P. gingivalis grown in brain heart infusion culture with or without d-val was inoculated in 24- or 96-well plates. After incubation for 72 hours, biomass via crystal violet staining, extracellular polysaccharide production by biofilms, and scanning electron microscopy (SEM) were used to determine the d-val concentration that can effectively prevent P. gingivalis biofilm formation. RESULTS: Experimental results showed that d-val effectively inhibited biofilm formation at concentrations ≥50 mM (mMol/L), and that d-val inhibition increased with increased concentration. Moreover, at high concentrations, the bacterial form changed from the normal baseball form into a rodlike shape. d-val also notably affected extracellular polysaccharide production by P. gingivalis. CONCLUSIONS: d-val can inhibit P. gingivalis biofilm formation, and high concentrations can affect bacterial morphology.