Electroacupuncture attenuates nociceptive behaviors in a mouse model of cancer pain.

Pain is a major symptom in cancer patients, and cancer-induced bone pain (CIBP) is the most common type of moderate and severe cancer-related pain. The current available analgesic treatments for CIBP have adverse effects as well as limited therapeutic effects. Acupuncture is proved effective in pain management as a safe alternative therapy. We evaluated the analgesic effect of acupuncture in treatment of cancer pain and try to explore the underlying analgesic mechanisms. Nude mice were inoculated with cancer cells into the left distal femur to establish cancer pain model. Electroacupuncture (EA) treatment was applied for the xenograft animals. Pain behaviors of mice were evaluated, followed by the detections of neuropeptide-related and inflammation-related indicators in peripheral and central levels. EA treatment alleviated cancer-induced pain behaviors covering mechanical allodynia, thermal hyperalgesia and spontaneous pain, and also down-regulated immunofluorescence expressions of neuropeptide CGRP and p75 in the skin of affected plantar area in xenograft mice, and inhibited expressions of overexpressed neuropeptide-related and inflammation-related protein in the lumbar spinal cord of xenograft mice. Overall, our findings suggest that EA treatment ameliorated cancer-induced pain behaviors in the mouse xenograft model of cancer pain, possibly through inhibiting the expressions of neuropeptide-related and inflammation-related protein in central level following tumor cell xenografts.

Design and synthesis of pyridin-2-yloxymethylpiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication.

A novel series of CCR5 antagonists were identified based on the redesign of Schering C. An SAR was established based on inhibition of CCR5 (RANTES) binding and these compounds exhibited potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells.

Design and synthesis of pyridin-2-ylmethylaminopiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication.

A series of CCR5 antagonists were optimized for potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells. Compounds that met acceptable ADME criteria, selectivity, human plasma protein binding, potency shift in the presence of α-glycoprotein were evaluated in rat and dog pharmacokinetics.

Survival analysis and treatment strategies for limb liposarcoma patients with metastasis at presentation.

ABSTRACT: Limited data exist on patients with limb liposarcoma (LLS) with metastasis at presentation Moreover, the potential prognostic factors of this patient population are poorly documented because of its rarity. Therefore, we conducted this study to evaluate the clinicopathologic characteristics and prognostic factors for patients with metastatic LLS.All patients with LLS with metastasis at presentation from 1975 to 2016 were identified by using the Surveillance, Epidemiology, and End Results (SEER) database. The following clinical data were derived from this clinical database: age, sex, histologic grade, subtype, size of tumor, surgery, radiotherapy, chemotherapy, vital status, cause of death, and survival duration. The Kaplan-Meier method was performed to calculate median survival time and draw survivorship curves. Cox-proportional hazards regression model was used to reveal the statistical independence between various variables.The present study collected 184 cases from SEER database for survival analysis. Mean age was 57.8 years with 63.6% (n = 117) men. The 3-year overall survival (OS) and cancer-specific survival (CSS) rates of this population were 27.8% and 30.1%, respectively. Univariate analysis revealed that age, tumor grade, and surgery were significantly correlated with survival. Sex and tumor size did not reach significant predictor status of survival. Multivariate analysis revealed that age at diagnosis <60, low tumor grade, and local surgery were significantly correlated with improved OS and CSS.Patients with LLS with metastasis at diagnosis experienced quite poor prognosis. Currently, surgery for the primary tumor significantly prolonged the survival of those patients, whereas chemotherapy and radiotherapy need to be further confirmed.

Establishing a novel prognostic tool for Ewing sarcoma patients: Surveillance, Epidemiology, and End Results database analysis.

Patients diagnosed with Ewing sarcoma (ES) usually experience poor outcomes. Accurate prediction of ES patients' prognosis is essential to improve their survival. Given that ES is a relatively rare tumor with a low incidence, we aim at developing a prognostic nomogram of ES patients based on a large sample analysis.We used the Surveillance, Epidemiology, and End Results (SEER) database to screen eligible patients diagnosed ES of bone. This retrospective study presented the clinicopathological characteristics and prognosis of ES. We randomly assigned all ES patients to 2 sets (training set and validation set) with an equal number of patients. In order to identify independent factors of survival, we performed univariate and multivariate Cox analysis in the training set. Then, we constructed novel nomograms to predict survival of ES patients by integrating significant independent variables from the training set. The prognostic performance of constructed nomograms was examined using concordance index (C-index) and calibration curves in both training and validation set.We included a total of 988 eligible cases diagnosed ES of bone between 2000 and 2015. Age >18 years, distant metastasis, tumor size >10 cm, and no surgery were independent risk factors for poorer survival. Our survival prediction nomograms were established based on those 4 independent risk factors. Good calibration plots were achieved in internal and external validation. The internal validation C-indexes of the nomogram for overall survival (OS) and cancer-specific survival (CSS) were 0.733 and 0.737, respectively. Similar good results were also achieved in external validation setting.The established nomograms show good performance and allow for better evaluating the prognosis of ES patients and recommending appropriate instructions.

Treatment of limb synovial sarcoma with metastasis at presentation.

Limb synovial sarcoma (LSS) patients with metastasis at presentation usually have a very poor prognosis. Little is known about survival prediction and risk factors in these patients owing to the condition's rarity. Thus, this study examined the survival and prognostic variables of metastatic LSS.Clinical data for LSS patients with metastasis at presentation from 1975 to 2016 were obtained from the surveillance, epidemiology, and end results database. The Kaplan-Meier method was used to determine the survival curves. Univariate and multivariate Cox regression analysis were conducted to identify the prognostic predictors.The study enrolled 217 patients. Male predominance was observed in the metastatic LSS group. The median age at diagnosis of this population was 40 years. The subtypes were "not otherwise specified" (49.8%), spindle cell (32.7%), biphasic (17.1%), and epithelioid cell (0.5%). The 3-year overall and cancer-specific survival rates of the entire group were 27.2% and 28.3%, respectively. Tumor size <10 cm, surgery, radiotherapy, and chemotherapy were independent predictors of improved overall and cancer-specific survival in the multivariate analyses.Comprehensive treatment for LSS patients with metastasis at diagnosis is necessary and effective and can prolong survival.

TFAP2C-mediated LINC00922 signaling underpins doxorubicin-resistant osteosarcoma.

Long noncoding RNAs (lncRNAs) have been indicated as critical regulators in osteosarcoma (OS). However, the function of lncRNAs in doxorubicin (DXR)-resistant OS remain unclear. Here, present study investigated the functions of lncRNA LINC00922 on the DXR resistance in OS tumorigenesis. LncRNA expression profile was detected using lncRNA microarray in DXR-resistant OS cells (MG63/DXR) and parental cells (MG63). Molecular binding was detected using luciferase reporter assay and chromatin immunoprecipitation. DXR sensitivity assay was detected using CCK-8 assay. Results showed that LINC00922 was significantly up-regulated in OS tissue specimens. Cellular assays showed that LINC00922 increased DXR IC50 and the knockdown of LINC00922 repressed the tumor growth of OS cells. Mechanistic assays showed that LINC00922 acts as a sponge of miR-424-5p, and miR-424-5p targeted the 3'-untranslated region of transcription factor activating protein 2 gamma (TFAP2C) mRNA. Moreover, TFAP2C promoted transcription of LINC00922 in a positive feedback loop comprising TFAP2C, LINC00922, and miR-424-5p. Collectively, these findings uncovered the function of TFAP2C/LINC00922/miR-424-5p feedback loop in DXR resistance, suggesting new therapeutic direction for OS.

Clinical features and prognostic analysis of patients with chest wall chondrosarcoma.

Chest wall chondrosarcoma is a rare malignant tumor of the bone. This study is aimed to identify the prognostic determinants of chest wall chondrosarcoma. We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with chest wall chondrosarcoma from 1973 to 2015. Statistical analyses were performed using Kaplan-Meier method and Cox regression proportional hazards. A total of 779 patients were identified from the SEER database. The overall survival (OS) and cancer-specific survival (CSS) rates of the entire group at 10 years were 66.2% and 77.2%, respectively. On multivariate Cox regression, age ≤40 years, localized tumor stage, low tumor grade, surgery, and no radiotherapy were significantly associated with improved both OS and CSS. This study may help clinicians to predict survival of patients with chest wall chondrosarcoma and to provide appropriate treatment recommendations.

Predictors of the Survival of Primary and Secondary Older Osteosarcoma Patients.

Purpose: Older osteosarcoma patients have a very poor prognosis and treatment for them remains a challenge. The outcomes and potential prognostic factors of primary or secondary older osteosarcoma patients are rarely documented. Therefore, we examined the prognosis of the two special cohorts to identify possible prognostic factors, and provide optimal treatment strategy for them. Methods: The Surveillance, Epidemiology, and End Results (SEER) program database was used to identify osteosarcoma patients aged over 40 years from 1973 to 2015. The prognostic analysis was performed using the Kaplan-Meier method and a Cox proportional hazards regression model. Results: In total, 1162 primary older osteosarcoma patients and 444 secondary older osteosarcoma patients were eligible for this study. The OS and CSS rates of the primary older osteosarcoma patients at 5-year were 38.5% and 37.1%, respectively. The 3- and 5-year OS rates of the secondary older osteosarcoma patients were 22.8% and 14.6%, respectively. On multivariate analysis of the primary older osteosarcoma patients, age > 60, male, axial site, high grade, metastasis, tumor size>10 cm, no surgery, and radiation treatment were negatively associated with OS. In terms of CSS, age, gender, decade of diagnosis, tumor site, tumor grade, tumor stage, tumor size, and surgery were independent prognostic factors. A multivariate Cox regression model showed that secondary older osteosarcoma patients of high grade, metastasis, tumor size > 10 cm, no surgery, and no chemotherapy were independent predictors of decreased OS. Conclusions: Surgery in combination with chemotherapy should be recommended for the treatment of the secondary older osteosarcoma patients, while for the primary older osteosarcoma patients, only surgery should be recommended.

Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies.

Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.

Synthesis of the Angiotensin-Converting Enzyme Inhibitors (-)-A58365A and (-)-A58365B from a Common Intermediate.

(-)-A58365A (1) and (-)-A58365B (2), which are inhibitors of angiotensin-converting enzyme, were synthesized from the subunits 9 and 10. These were coupled, and the resulting individual amides 17a,b were converted by ozonolysis into aldehydes 18a,b, which underwent cyclodehydration to the enamides 19a,b. Treatment with a stannane served to generate the vinyl stannanes 20a,b, from which ketones 22a,b were produced by protodestannylation and ozonolysis. Base treatment and hydrogenolysis then afforded (-)-A58365A (1). The intermediates 17a,b were also converted into aldehydes 26a,b by hydroboration and oxidation, and a similar sequence to that used for (-)-A58365A was then applied in order to complete the first enantiospecific synthesis of the congener, (-)-A58365B (2).

Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.

The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.

Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication.

A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels.

Synthesis and structure-activity relationships of azamacrocyclic C-X-C chemokine receptor 4 antagonists: analogues containing a single azamacrocyclic ring are potent inhibitors of T-cell tropic (X4) HIV-1 replication.

Bis-tetraazamacrocycles such as the bicyclam AMD3100 (1) are a class of potent and selective anti-HIV-1 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the coreceptor for entry of X4 viruses. By sequential replacement and/or deletion of the amino groups within the azamacrocyclic ring systems, we have determined the minimum structural features required for potent antiviral activity in this class of compounds. All eight amino groups are not required for activity, the critical amino groups on a per ring basis are nonidentical, and the overall charge at physiological pH can be reduced without compromising potency. This approach led to the identification of several single ring azamacrocyclic analogues such as AMD3465 (3d), 36, and 40, which exhibit EC(50)'s against the cytopathic effects of HIV-1 of 9.0, 1.0, and 4.0 nM, respectively, antiviral potencies that are comparable to 1 (EC(50) against HIV-1 of 4.0 nM). More importantly, however, the key structural elements of 1 required for antiviral activity may facilitate the design of nonmacrocyclic CXCR4 antagonists suitable for HIV treatment via oral administration.

Discovery of novel small molecule orally bioavailable C-X-C chemokine receptor 4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication.

The redesign of azamacrocyclic CXCR4 chemokine receptor antagonists resulted in the discovery of novel, small molecule, orally bioavailable compounds that retained T-tropic (CXCR4 using, X4) anti-HIV-1 activity. A structure-activity relationship (SAR) was determined on the basis of the inhibition of replication of X4 HIV-1 NL4.3 in MT-4 cells. As a result of lead optimization, we identified (S)-N'-((1H-benzo[d]imidazol-2-yl)methyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (AMD070) 2 as a potent and selective antagonist of CXCR4 with an IC(50) value of 13 nM in a CXCR4 125I-SDF inhibition binding assay. Compound 2 inhibited the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC(50) of 2 and 26 nM, respectively, while remaining noncytotoxic to cells at concentrations exceeding 23 microM. The pharmacokinetics of 2 was evaluated in rat and dog, and good oral bioavailability was observed in both species. This compound represents the first small molecule orally bioavailable CXCR4 antagonist that was developed for the treatment of HIV-1 infection.

Palladium(0)-catalyzed coupling of organozinc iodide reagents with bromopyridines: synthesis of selectively protected pyridine-containing azamacrocycles.

The synthesis of azamacrocycles in which the ring nitrogens are regioselectively functionalized is described. An organozinc palladium(0)-catalyzed coupling with an appropriately functionalized bromopyridine generated a key intermediate, which was transformed in two steps to a desired precursor and subjected to an intramolecular N-alkylation to effect a macrocyclization affording selectively protected azamacrocycles 1-3.