Discovery of a Highly Potent Oxysterol Receptor GPR183 Antagonist Bearing the Benzo[d]thiazole Structural Motif for the Treatment of Inflammatory Bowel Disease (IBD).

Accumulating evidence has demonstrated a critical pathological role of oxysterol receptor GPR183 in various inflammatory and autoimmune diseases, including inflammatory bowel disease (IBD). However, the currently reported GPR183 antagonists are very limited and not qualified for in vivo studies due to their inferior druglike properties. Herein, we conducted a structural elaboration focusing on improving its PK and safety profile based on a reference antagonist NIBR189. Of note, compound 33, bearing an aminobenzothiazole motif, exhibited reduced hERG inhibition, improved PK properties, and robust antagonistic activity (IC50 = 0.82 nM) with high selectivity against GPR183. Moreover, compound 33 displayed strong in vitro antimigration and anti-inflammatory activity in monocytes. Oral administration of compound 33 effectively improved the pathological symptoms of DSS-induced experimental colitis. All of these findings demonstrate that compound 33 is a novel and promising GPR183 antagonist suitable for further investigation to treat IBD.

Discovery of Pyridinone Derivatives as Potent, Selective, and Orally Bioavailable Adenosine A2A Receptor Antagonists for Cancer Immunotherapy.

Recent studies and clinical evidence have strongly supported the development of adenosine A2A receptor (A2AR) antagonists as novel approaches for cancer immunotherapy. By screening our in-house compound library, a pyridinone hit compound (1) with weak A2AR antagonistic activity was identified. Further structure-activity relationship studies revealed a series of pyridinone derivatives with strong potency. Compound 38 stood out with a potent A2AR antagonistic activity (IC50 = 29.0 nM), good mouse liver microsomal metabolic stability (t1/2 = 86.1 min), and excellent oral bioavailability (F = 86.1%). Of note, 38 effectively enhanced the activation and killing ability of T cells in vitro by down-regulation of immunosuppressive molecules (LAG-3 and TIM-3) and up-regulation of effector molecules (GZMB, IFNG, and IL-2). Moreover, 38 exhibited excellent in vivo antitumor activity with a tumor growth inhibition (TGI) of 56.0% in the MC38 tumor model via oral administration, demonstrating its potential as a novel A2AR antagonist candidate for cancer immunotherapy.

A Novel Small Molecular Prostaglandin Receptor EP4 Antagonist, L001, Suppresses Pancreatic Cancer Metastasis.

Metastatic pancreatic cancer remains a major clinical challenge, emphasizing the urgent need for the exploitation of novel therapeutic approaches with superior response. In this study, we demonstrate that the aberrant activation of prostaglandin E2 (PGE2) receptor 4 (EP4) is a pro-metastatic signal in pancreatic cancer. To explore the therapeutic role of EP4 signaling, we developed a potent and selective EP4 antagonist L001 with single-nanomolar activity using a panel of cell functional assays. EP4 antagonism by L001 effectively repressed PGE2-elicited cell migration and the invasion of pancreatic cancer cells in a dose-dependent manner. Importantly, L001 alone or combined with the chemotherapy drug gemcitabine exhibited remarkably anti-metastasis activity in a pancreatic cancer hepatic metastasis model with excellent tolerability and safety. Mechanistically, EP4 blockade by L001 abrogated Yes-associated protein 1 (YAP)-driven pro-metastatic factor expression in pancreatic cancer cells. The suppression of YAP's activity was also observed upon L001 treatment in vivo. Together, these findings support the notions that EP4-YAP signaling axis is a vital pro-metastatic pathway in pancreatic cancer and that EP4 inhibition with L001 may deliver a therapeutic benefit for patients with metastatic pancreatic cancer.

Hemophagocytic lymphohistiocytosis secondary to Candida albicans and reactivated EBV infections: A case report and review of the literature.

Hemophagocytic lymphohistiocytosis (HLH) has been recognized as a potentially life-threatening syndrome. This is the first case of acquired HLH caused by dual infections with Candida albicans and reactivated EBV infections, which focuses on the importance of morphological awareness of peripheral blood and bone marrow because sometimes they are the only locations that HLH and fungal microorganisms can be diagnosed. A 29-year-old woman with a history of abdominal distension and 9 months of intermittent fevers ($38.8°C) was admitted to the hematology department with treatment for leukopenia and thrombocytopenia. Severe infection of bilateral pulmonary and marked hepatosplenomegaly were detected by computed tomography. EB virus-CA IgG, EB virus-NA IgG and EB virus-CA IgM were positive. Scattered yeast-like fungi were found on peripheral blood and bone marrow (BM) smears. BM smears indicated prominent hemophagocytosis. Cultures of bronchoalveolar lavage and BM confirmed the growth of C. albicans. A diagnosis of HLH caused by dual infections with Candida albicans and reactivated EBV infections was established based on the clinical features of the patient because 7 of the 8 diagnostic criteria were met. She was treated with etoposide, dexamethasone for HLH, as well as highly active antifungal and antiviral therapies for the underlying etiology of dual infections. The patient eventually recovered following the effective treatment. A timely and accurate diagnosis is crucial to the prognosis of the dangerous disease.

From a Designer Drug to the Discovery of Selective Cannabinoid Type 2 Receptor Agonists with Favorable Pharmacokinetic Profiles for the Treatment of Systemic Sclerosis.

Synthetic cannabinoids, as exemplified by SDB-001 (1), bind to both CB1 and CB2 receptors and exert cannabimimetic effects similar to (-)-trans-Δ9-tetrahydrocannabinol, the main psychoactive component present in the cannabis plant. As CB1 receptor ligands were found to have severe adverse psychiatric effects, increased attention was turned to exploiting the potential therapeutic value of the CB2 receptor. In our efforts to discover novel and selective CB2 receptor agonists, 1 was selected as a starting point for hit molecule identification and a class of 1H-pyrazole-3-carboxamide derivatives were thus designed, synthesized, and biologically evaluated. Systematic structure-activity relationship investigations resulted in the identification of the most promising compound 66 as a selective CB2 receptor agonist with favorable pharmacokinetic profiles. Especially, 66 treatment significantly attenuated dermal inflammation and fibrosis in a bleomycin-induced mouse model of systemic sclerosis, supporting that CB2 receptor agonists might serve as potential therapeutics for treating systemic sclerosis.

Atypical Acute Monocytic Leukemia: a Lymphoma Presentation and Association with Complex Karyotype.

A 71-year-old woman presented with acute monocytic leukemia with lymphoma-like morphologic features and an unusual complex karyotype. Bone marrow (BM) aspiration revealed acute monocytic leukemia with lymphoma-like morphologic features. Thus, we called the condition a lymphoma presentation. The patient was diagnosed with acute monocytic leukemia (AML FAB M5a) according to the French-American-British (FAB) classification and the new World Health Organization (WHO) classification [1]. To our knowledge, this is the first reported case of an unusual complex karyotype in acute monocytic leukemia with a lymphoma presentation and adds to the expanding list of karyotypic abnormalities seen in acute monocytic leukemia. We present the case given its rarity, occasional misdiagnosis and poor prognosis. Whether this complex karyotype resulted in such lymphoma-like morphologic features remains to be determined. The case illustrates the importance of the morphologic features cognition and avoiding misdiagnosis. Clinical trials are available to further explore how to extend survival time and contribute to a better prognosis for patients suffering from acute monocytic leukemia with a complex karyotype.

Reductive dechlorination and mineralization of pentachlorophenol in biocathode microbial fuel cells.

Simultaneous anaerobic and aerobic degradation pathways in two-chamber, tubular microbial fuel cells (MFCs) facilitated pentachlorophenol (PCP) mineralization by a mediator-less biocathode. PCP was degraded at a rate of 0.263 ± 0.05 mg/L-h (51.5 mg/g VSS-h) along with power generation of 2.5 ± 0.03 W/m(3). Operating the biocathode MFC at 50°C improved the PCP degradation rate to 0.523 ± 0.08 mg/L-h (103 mg/g VSS-h) and power production to 5.2 ± 0.03 W/m(3). A pH of 6.0 increased the PCP degradation rate to 0.365 ± 0.02 mg/L-h (71.5mg/g VSS-h), but reduced power. While mediators were not needed, adding anthraquinone-2,6-disulfonate increased power and PCP degradation rates. Dominant bacteria most similar to the anaerobic Desulfobacterium aniline, Actinomycetes and Streptacidiphilus, and aerobic Rhodococcus erythropolis, Amycolatopsis and Gordonia were found on the biocathode. These results demonstrate efficient degradation of PCP in biocathode MFCs and the effects of temperature, pH and mediators.

Effect of set potential on hexavalent chromium reduction and electricity generation from biocathode microbial fuel cells.

Setting a biocathode potential at -300 mV improved the subsequent performance of an MFC for Cr(VI) reduction compared to a control (no set potential). With this set potential, the startup time was reduced to 19 days, the reduction of Cr(VI) was improved to 19.7 mg/L d, and the maximum power density was increased to 6.4 W/m(3) compared to the control (26 days, 14.0 mg/L d and 4.1 W/m(3)). Set potentials of -150 mV and -300 mV also improved system performance and led to similarly higher utilization of metabolic energy gained (PMEG) than set potentials of +200 mV and -450 mV. We observed putative pili at -150 and -300 mV potentials, and aggregated precipitates on bacterial surfaces in both poised and nonpoised controls. These tests show that there are optimal potentials that can be set for developing a Cr(VI) biocathode.