Discovery of Novel Azaindoles as Potent and Selective PI3Kδ Inhibitors for Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system and the unmet need for MS treatment demands new therapeutic development. Particularly, PI3Kδ is a high-value target for autoimmune disease, while the investigation of PI3Kδ inhibitors for MS therapy is relatively scarce. Herein, we report a novel class of azaindoles as PI3Kδ inhibitors for MS treatment.

Discovery of Potent and Selective PI3Kδ Inhibitors for the Treatment of Acute Myeloid Leukemia.

PI3Kδ is an essential target correlated to the occurrence and development of acute myeloid leukemia (AML). Herein, we investigated the pyrazolo[3,4-]pyrimidine derivatives as potent and selective PI3Kδ inhibitors with high therapeutic efficacy toward AML. There were 44 compounds designed and prepared in a four-round optimization, and the biological evaluation showed that exhibited potent PI3Kδ inhibitory activity, high selectivity, and high antiproliferative activities against MV-4-11 and MOLM-13 cells, coupled with high oral bioavailability ( = 59.

A Pan-Cancer Analysis of the Immunological and Prognostic Role of BUB1 Mitotic Checkpoint Serine/Threonine Kinase B (BUB1B) in Human Tumors.

Background: BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) is a member of the spindle assembly checkpoint family and is related to cancer disease progression, invasion, metastasis, and functional promotion of angiogenesis. Several studies have noted that the BUB1B gene is frequently upregulated in various types of cancers. However, the expression patterns of BUB1B across different cancer types and its diagnostic and prognostic potential have not been investigated from a pan-cancer perspective.

Construction of ceRNA Regulatory Network in Human Oocytes.

Background: Cryogenic freezing, often known as cryopreservation, is a technique for preserving human oocytes.

Methods: In this study, differentially expressed long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) were identified using the human frozen oocyte dataset GSE69768 from the Gene Expression Database (GEO). Subsequently, combined with the microRNA atlas database, the miRNAs combined with differentially expressed lncRNAs (DElncRNAs) were predicted, and the lncRNA-miRNA-mRNA interaction relationship and competitive endogenous (ceRNA) regulatory network were obtained.

Discovery of Highly Selective and Orally Bioavailable PI3Kδ Inhibitors with Anti-Inflammatory Activity for Treatment of Acute Lung Injury.

PI3Kδ is a promising target for the treatment of inflammatory disease; however, the application of PI3Kδ inhibitors in acute respiratory inflammatory diseases is rarely investigated. In this study, through scaffold hopping design, we report a new series of 1-pyrazolo[3,4-]pyrimidin-4-amine-tethered 3-methyl-1-aryl-1-indazoles as highly selective and potent PI3Kδ inhibitors with significant anti-inflammatory activities for treatment of acute lung injury (ALI). There were 29 compounds designed, prepared, and subjected to PI3Kδ inhibitory activity evaluation and anti-inflammatory activity evaluation in macrophages.

The Mediating Role of Systemic Inflammation in the Effects of Fetal Famine Exposure on Cardiovascular Disease in Adults: A Cohort Study.

Background: A few studies have reported the association between famine exposure during fetal development and risk of CVD, but no mechanisms have been explored.

Objectives: The objective of this study was to examine risk of CVD in adulthood after exposure to famine during the fetal stage and explore the mediating role of systemic inflammation.

Methods: A total of 59,416 participants of the Kailuan Study without CVD were included.

Increased expression of TBC1D10B as a potential prognostic and immunotherapy relevant biomarker in liver hepatocellular carcinoma.

The TBC1 domain family member 10B (EPI64B/TBC1D10B), a member of the RabGAP EPI64 subfamily, contains a TBC domain that confers GTPase-activating protein activity. Even though overexpression of TBC1D10B has been reported to promote tumor invasion and metastasis in gastric adenocarcinoma, the prognostic value of TBC1D10B and its correlation with DNA methylation and immune infiltration in hepatocellular carcinoma are still not known. Transcriptional expression profiles of TBC1D10B between hepatocellular carcinoma tissues and normal tissues were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus.

Association Between Fresh Embryo Transfers and Frozen-Thawed Embryo Transfers Regarding Live Birth Rates Among Women Undergoing Long Gonadotropin-Releasing Hormone Antagonist Protocols.

The availability and use of frozen-thawed embryos after controlled ovarian hyperstimulation for assisted reproduction have increased with improvements in vitrification techniques and the rise of gonadotropin-releasing hormone (GnRH) antagonist protocols. Although evidence has shown that frozen-thawed embryo transfers (FETs) result in higher live birth rates than fresh embryo transfers, it is uncertain whether this association exists in cycles employing the GnRH antagonist protocol. To test the hypothesis that FETs are more likely to result in a live birth than fresh embryo transfers in a GnRH antagonist protocol cycle and to investigate whether frozen blastocyst transfer increases live birth rates compared to fresh blastocyst transfer.

Discovery of Novel Indazoles as Potent and Selective PI3Kδ Inhibitors with High Efficacy for Treatment of Hepatocellular Carcinoma.

PI3Kδ inhibitors have been developed for treatment of B-cell malignancies and inflammatory and autoimmune diseases. However, their therapeutic role in solid tumors like hepatocellular carcinoma (HCC) is rarely reported. Thus, the development of potent and selective PI3Kδ inhibitors with a new chemotype and therapy is highly desirable.

A Pan-Cancer Analysis of the Oncogenic Role of Integrin Beta4 (ITGB4) in Human Tumors.

Background: Integrin beta4 (ITGB4) is a transmembrane receptor that plays a key role in tumorigenesis and tumor development. However, there are no pan-cancer analyses of ITGB4.

Methods: This study demonstrates the first potential oncogenic roles of ITGB4 across 33 tumors based on the dataset of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO).

Comparison of Electrocoagulation Tuboplasty and Continued Medical Therapy for Treating Persistent Eustachian Tube Dysfunction With Hypertrophic Mucosa Disease.

Objectives: The objective of this trial was to compare outcomes of electrocoagulation tuboplasty and continued medical therapy for treating persistent Eustachian tube dysfunction (ETD) with hypertrophic mucosa disease in the Eustachian tube (ET) orifice.

Study Design: Prospective, case-control trial.

Material And Methods: Patients with persistent ETD were recruited and allocated to electrocoagulation tuboplasty and continued medical therapy groups.

Is no de-squamatization of the TM reliable for cartilage over-underlay myringoplasty without external auditory canal packing?

Objective: We evaluated the graft and hearing outcomes of patients with chronic perforations treated via the cartilage-perichondrium over-underlay technique without de-squamatization of the TM and external auditory canal (EAC) packing.

Materials And Methods: Thirty-nine patients with chronic perforations and residual tympanic membranes around the perforation margins were treated using the cartilage-perichondrium over-underlay technique without de-squamatization of the TM and EAC packing. Patients were followed-up for 6 months.

[Dietary quality among heat-exposed steelworkers in Tangshan City in 2015].

Objective: To evaluate the dietary quality and find the dietary problems among heat-exposed steelworkers.

Methods: During May and June of 2015, 301 heat-exposed steelworkers were recruited using a cluster sampling method from three workshops in steel works of the Tangshan Iron & Steel Group. In the study, 3 day twentyfour hour(24 h) recall method was used to conduct the dietary survey.

Discovery of novel inhibitors of phosphodiesterase 4 with 1-phenyl-3,4-dihydroisoquinoline scaffold: Structure-based drug design and fragment identification.

Currently, it is in urgent need to develop novel selective PDE4 inhibitors with novel structural scaffolds to overcome the adverse effects and improve the efficacy. Novel 1-phenyl-3,4-dihydroisoquinoline amide derivatives were developed as potential PDE4 inhibitors based on the structure-based drug design and fragment identification strategy. A SARs analysis was performed in substituents attached in the C-3 side chain phenyl ring, indicating that the attachment of methoxy group or halogen atom substitution at the ortho-position of the phenyl ring was helpful to enhance both inhibitory activity toward PDE4B and selectivity.

Synthesis and bioactivity of 3,5-dimethylpyrazole derivatives as potential PDE4 inhibitors.

A series of 3,5-dimethylpyrazole derivatives containing 5-phenyl-2-furan moiety were designed and synthesized as phosphodiesterase type 4 (PDE4) inhibitors. Bioassay results showed that the title compounds exhibited considerable inhibitory activity against PDE4B and blockade of LPS-induced TNFα release. Among the designed compounds, compound If showed the best inhibitory activity against PDE4B with the IC value of 1.

Structure-based design and structure-activity relationships of 1,2,3,4-tetrahydroisoquinoline derivatives as potential PDE4 inhibitors.

This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC of 0.

Design, Synthesis and Structure-Activity Relationship of Novel Aphicidal Mezzettiaside-Type Oligorhamnosides and Their Analogues.

Oligosaccharides have been used for an environmentally friendly insect control in the agricultural industry. In order to discover novel eco-friendly pesticides, a series of partially acetylated oligorhamnoses mezzettiasides, -, and their analogues, -, with biosurfactant characteristics were designed and synthesized, some of which exhibited comparable to or even stronger aphicidal activity than pymetrozine. Preliminary SAR studies demonstrated that the aphicidal activity of mezzettiasides analogs is highly dependent on their structures, including both the sugar length and the substitutes on the sugar.

[Effects of the nutritional education and dietary intervention on nutritional status and bone mineral density of middle-aged and senile patients with osteoporosis].

Objective: To study the effect of the nutritional education and dietary intervention on nutritional status and bone mineral density (BMD) of middle-aged and senile patients with osteoporosis.

Methods: Ninty middle-aged and senile osteoporosis patients were enrolled. They were randomly divided into two groups (intervention and control group) with 45 cases each.

Relationships between micronutrient losses in sweat and blood pressure among heat-exposed steelworkers.

We aimed to examine the effect of micronutrient losses through sweat on blood pressure (BP) among heat-exposed steelworkers. A total of 224 heat-exposed male steelworkers from an ironworks facility were evaluated in July 2012. We measured the Wet Bulb Globe Temperature Index to evaluate the level of heat stress in the workplace.

Risk factors affecting human traumatic tympanic membrane perforation regeneration therapy using fibroblast growth factor-2.

Objective: The use of growth factors to achieve closure of human traumatic tympanic membrane perforations (TMPs) has recently been demonstrated. However, pretreatment factors affecting healing outcomes have seldom been discussed. The objective of this study was to evaluate pretreatment factors contributing to the success or failure of healing of TMPs using fibroblast growth factor-2 (FGF-2).

Utility of basic fibroblast growth factor in the repair of blast-induced total or near-total tympanic membrane perforations: A pilot study.

Objective: A pilot study was performed to investigate the utility of basic fibroblast growth factor (bFGF) in the repair of blast-induced total or near-total tympanic membrane perforations (TMPs).

Study Design: Prospective clinical study.

Setting: Tertiary university hospital.

Comparative study on the effects of EGF and bFGF on the healing of human large traumatic perforations of the tympanic membrane.

Objectives/hypothesis: We evaluated the effects of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) on the healing of large traumatic tympanic membrane perforations (TMPs).

Study Design: Prospective clinical study.

Setting: Tertiary university hospital.

Relation between eardrum flap area and healing outcome of traumatic eardrum perforation.

Objective: To retrospectively study the clinical effects of eardrum flap area on the healing outcome following traumatic perforation.

Methods: Totally 291 traumatic eardrum perforations with in-/everted edges were included in this study. They were randomly divided into three groups and received conservative treatment, epidermal growth factor (EGF) via Gelfoam patching, or edge-approximation plus Gelfoam patching respectively.