Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in and .

Inosine 5'-monophosphate dehydrogenase (IMPDH), known as GuaB in bacteria, catalyzes the rate-limiting step in guanine biosynthesis and is conserved from humans to bacteria. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here, we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important Gram-negative pathogens: and .

Discovery of GuaB inhibitors with efficacy against infection.

Unlabelled: Guanine nucleotides are required for growth and viability of cells due to their structural role in DNA and RNA, and their regulatory roles in translation, signal transduction, and cell division. The natural antibiotic mycophenolic acid (MPA) targets the rate-limiting step in guanine nucleotide biosynthesis executed by inosine-5´-monophosphate dehydrogenase (IMPDH). MPA is used clinically as an immunosuppressant, but whether inhibition of bacterial IMPDH (GuaB) is a valid antibacterial strategy is controversial.

Impact assessment of metabolite instability in the development and validation of LC-MS/MS bioanalytical assays for measurement of rosuvastatin in human plasma and urine samples.

During bioanalytical assay development and validation, maintaining the stability of the parent drug and metabolites of interest is critical. While stability of the parent drug has been thoroughly investigated, the stability of unanalyzed metabolites is often overlooked. When an unstable metabolite is known or suspected to interfere with measurement of the parent drug or other metabolites of interest through back-conversion or other routes, additional tests with these unstable metabolites should be conducted.

A universal surrogate matrix assay for urea measurement in clinical pharmacokinetic studies of respiratory diseases.

In pharmacokinetic studies for respiratory diseases, urea is a commonly used dilution marker for volume normalization of various biological matrices, owing to the fact that urea diffuses freely throughout the body and is minimally affected by disease states. In this study, we developed a convenient liquid chromatography-tandem mass spectrometry (LC-MS/MS) surrogate matrix assay for accurate urea quantitation in plasma, serum and epithelial lining fluid. Different mass spectrometer platforms and ionization modes were compared in parallel.

First-in-human phase 1 trial evaluating safety, pharmacokinetics, and pharmacodynamics of NLRP3 inflammasome inhibitor, GDC-2394, in healthy volunteers.

Inappropriate and chronic activation of the cytosolic NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first-in-human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150-1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC-2394, a small-molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC-2394 and its CYP3A4 induction potential in food-effect (FE) and drug-drug interaction (DDI) stages, respectively.

Exploring the potential of dried plasma collection cards for liquid chromatography coupled with tandem mass spectrometry quantitation of giredestrant in human plasma.

Microsampling technology for dried blood-derived samples provides an advantageous alternative to conventional venous blood for drug quantitation. Unlike conventional whole blood microsampling techniques, Noviplex is a novel, card-based technology for rapid dried plasma spot collection that retains the benefits of microsampling during collection and transportation, while avoiding the disadvantages of using whole blood samples. Giredestrant is a promising small-molecule therapeutic agent under development by Genentech to treat patients with estrogen receptor-positive breast cancer.

Case report: Durable response to alectinib in -rearranged lung adenocarcinoma with acquired, crizotinib-resistant C1156F mutation.

Treatment of -rearranged non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitors (TKIs) is challenged by the almost inevitable emergence of therapeutic resistance. Different profiles of resistance mechanisms have been reported for the currently available ALK TKIs. The C1156Y mutation is reported in 2% of patients with acquired resistance to crizotinib.

Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC-0214 in healthy volunteers.

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo-controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC-0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule-based inhaler.

A technical overview of supercritical fluid chromatography-mass spectrometry (SFC-MS) and its recent applications in pharmaceutical research and development.

In this paper, we review the growing development and applications of supercritical fluid chromatography-mass spectrometry (SFC-MS) for the analysis of small molecular analytes and biomarkers in drug discovery. As an alternative chromatographic technique, SFC instrumentation and methodology have dramatically advanced over the last decade. Mass spectrometry (MS) provides the powerful detection capability as it couples with SFC.

Translational and pharmacokinetic-pharmacodynamic application for the clinical development of GDC-0334, a novel TRPA1 inhibitor.

GDC-0334 is a novel small molecule inhibitor of transient receptor potential cation channel member A1 (TRPA1), a promising therapeutic target for many nervous system and respiratory diseases. The pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of GDC-0334 were evaluated in this first-in-human (FIH) study. A starting single dose of 25 mg was selected based on integrated preclinical PK, PD, and toxicology data following oral administration of GDC-0334 in guinea pigs, rats, dogs, and monkeys.

A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment.

Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described.

Combination of traditional Chinese medicine and epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of non-small cell lung cancer: A systematic review and meta-analysis.

Background: In China, traditional Chinese medicine (TCM) is an increasingly important part of the treatment of non-small cell lung cancer (NSCLC), which usually includes a combination of prescription and syndrome differentiation. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been proven to be the first-line drugs for the treatment of advanced EGFR mutation-positive NSCLC. In China, EGFR-TKIs are used in combination with traditional Chinese medicines to reduce side effects and/or enhance effectiveness.

Validation of the NEOS score in Chinese patients with anti-NMDAR encephalitis.

Objective: The performance of anti-NMDAR Encephalitis One-Year Functional Status (NEOS) in predicting the 1-year functional status in Chinese patients with anti-NMDAR encephalitis is unknown.

Methods: We recruited patients with anti-NMDAR encephalitis from the Multicenter and Prospective Clinical Registry Study of Anti-NMDAR Encephalitis in Beijing Area. Patients were followed up for 1 year.

Correlation of PD-L1 and SOCS3 Co-expression with the Prognosis of Hepatocellular Carcinoma Patients.

To investigate the correlation between the expression of PD-L1, SOCS3 and immune-related biomarkers CD276, CD4, CD8 in hepatocellular carcinoma (HCC) and further determine the relationship with clinicopathologic characteristics and the prognostic value of their co-expression in HCC patients. We assessed the expression of PD-L1, CD276, SOCS3, CD4 and CD8 by immunohistochemistry in tumor tissue from 74 HCC patients who underwent curative hepatectomy. High expression of PD-L1 was significantly associated with high Edmondson grade (p<0.

β-Elemene Reverses the Resistance of p53-Deficient Colorectal Cancer Cells to 5-Fluorouracil by Inducing Pro-death Autophagy and Cyclin D3-Dependent Cycle Arrest.

Objective: Colorectal cancer is a malignant tumor of the digestive system with high morbidity and mortality. 5-fluorouracil remains a widely used chemotherapeutic drug in the treatment of advanced colorectal cancer, but chemotherapy drugs are prone to develop drug resistance, p53 deletion or mutation is an important reason for the resistance of colorectal cancer cells to 5-fluorouracil. β-elemene has been proved to have the potential of reverse chemotherapy drug resistance, but the mechanism is unknown.

Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis.

Ferroptosis, a novel form of programmed cell death, is characterized by iron-dependent lipid peroxidation and has been shown to be involved in multiple diseases, including cancer. Stimulating ferroptosis in cancer cells may be a potential strategy for cancer therapy. Therefore, ferroptosis-inducing drugs are attracting more attention for cancer treatment.

Combinative treatment of β-elemene and cetuximab is sensitive to KRAS mutant colorectal cancer cells by inducing ferroptosis and inhibiting epithelial-mesenchymal transformation.

: RAS mutations limit the effectiveness of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in combination with chemotherapy for metastatic colorectal cancer (mCRC) patients. Therefore, new cell death forms have focused on identifying indirect targets to inhibit Ras-induced oncogenesis. Recently, emerging evidence has shown the potential of triggering ferroptosis for cancer therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies.

Efficacy and safety of elemene combined with chemotherapy in advanced gastric cancer: A Meta-analysis.

Background: Elemene is a natural compound extracted from Zingiberaceae plants, and is used in various cancer. However, the efficacy and safety elemene combined with chemotherapy in advanced gastric cancer (GC) are lack of systematic assessment.

Methods: we searched the PubMed, EMBASE, Web of Science, Cochrane Library, China Academic Journals (CNKI), Chinese Science and Technology Journals (CQVIP) and Chinese Biomedical Literature databases.

PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death.

5-Fluorouracil (5-FU) is known as a first-line chemotherapeutic agent against colorectal cancer (CRC), but drug resistance occurs frequently and significantly limits its clinical success. Our previous study showed that the protocadherin 17 () gene was frequently methylated and functioned as a tumor suppressor in CRC. However, the relationship between and 5-FU resistance in CRC remains unclear.

p53/PCDH17/Beclin-1 Proteins as Prognostic Predictors for Urinary Bladder Cancer.

To determine whether p53, PCDH17, Beclin-1 expression is associated with clinicopathological characteristics of bladder cancer. 75 patients with non-muscle-invasive and muscle-invasive bladder cancer were included. Immunohistochemical staining for p53, PCDH17 and Beclin-1 were carried out on the same paraffin-embedded blocks serial sections of these patients who underwent surgery between 2010 and 2015.

Changes in Organic Anion Transporting Polypeptide Uptake in HEK293 Overexpressing Cells in the Presence and Absence of Human Plasma.

Generating accurate in vitro data is crucial for in vitro to in vivo extrapolation and pharmacokinetic predictions. The use of human embryonic kidney (HEK) 293 cells overexpressing organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 in protein-free buffer and 100% human plasma incubations was explored for the uptake of four OATP substrates: pravastatin, rosuvastatin, repaglinide, and pitavastatin. Differences were observed for each parameter [unbound Michaelis constant ( ), , intrinsic clearance (CL), and unbound passive diffusion P] obtained from the buffer and plasma incubations in both cells, and the fold differences were greatest for the highly protein bound compounds.

Evaluation of polysaccharide-based chiral stationary phases in modern SFC-MS/MS for enantioselective bioanalysis.

The applicability of polysaccharide-based chiral stationary phases in modern supercritical fluid chromatography (SFC)-MS/MS for chiral bioanalysis was evaluated. Ten popular polysaccharide-based chiral stationary phases (CSPs) were tested using a set of 23 drugs against three cosolvents. The effect of temperature and backpressure on separation was examined.