The EZMTT cell proliferation assay provides precise measurement for drug combinations and better correlation between in vitro and in vivo efficacy.

The rate of drug-induced proliferation (DIP) has been proposed as an unbiased alternative drug effect metric. However, current assays are not easy and precise enough to track minor changes in cell growth. Here, we report the optimized EZMTT based detection method which can continuously measure time-dependent growth after drug treatment and reliably detect partial drug resistance for cancer cells. Importantly, tracking time-dependent growth after drug treatment demonstrated that a KGA allosteric inhibitor alone failed to completely inhibit cancer cell growth, but a drug combination was able to provide complete inhibition in cell-based assays that translated well in in vivo animal experiments. In conclusion, this simple EZMTT method provided precise measurement of loss of susceptibility after drug treatment and has great potential to be developed for drug efficacy and drug combination studies to solve the unmet medical need.

Design and synthesis of novel tellurodibenzoic acid compounds as kidney-type glutaminase (KGA) inhibitors.

Organotellurium compounds have been reported as an immune-modulator sensitizing chemotherapeutics. Herein, we report the design and synthesis of a series of novel tellurodibenzoic acids as mimics of diphenylarsenic acid (DPAA) and potential selective KGA inhibitors. Representative compound 3B exhibited potent inhibition of KGA and glutamine-dependent HCT-116 cells. Stability experiments indicated that 3B has excellent stability under acidic (HCOOH), basic (NH3·H2O) and oxidative (H2O2) conditions, but reacts with ß-ME, DTT and lysine which suggested that compound 3B may interact with cysteine or lysine residues. Moreover, molecular docking disclosed that compound 3B binds to the allosteric site of the GAC tetramer containing Arg317-Lys320-Leu321-Phe322-Tyr394-Glu325, which helped to rationalize the SAR and further design and optimization. Taken together, compound 3B could be used as a starting point for the development of new KGA inhibitors.

A Cross-Sectional Study on the Application of IS in Perioperative Pulmonary Function Training in Spine and Orthopedics.

Background: The incentive spirometer (IS) is a mechanical device that promotes lung expansion and can be used to prevent and treat postoperative pulmonary complications. In this study, the preventive effect of pulmonary function training with IS on the improvement of pulmonary function and pulmonary complications was observed. Methods: From May 2019 to April 2021, 69 scoliosis patients with impaired moderate and severe lung function were divided into the traditional pulmonary training group (n = 32) and IS-enhanced pulmonary training group (n = 35). The patient underwent lung function testing after admission and one week after the start of training and chest CT on the third day after surgery. Results: The average age was 13.47 and 15.66, respectively (p = 0.223). The Cobb angles were 83.84 and 83.97 (p = 0.756), respectively, and no statistical difference between the parameters of lung function was detected. After 1 week of respiratory function training, significant improvement in lung function testing parameters including VC%, FVC%, FEV1%, FEV1/FVC, FEV1/VC, and MVV% was found in both groups. Analysis of covariance showed more significant improvement in IS-enhanced group compared to the conventional training group (p < 0.05). The incidence of postoperative pulmonary atelectasis was lower in IS-enhanced group than in traditional groups (2.9% vs. 21.9%, p = 0.043) with no difference in the overall incidence of pulmonary complications (p = 0.164) and shorter preoperative and total hospitalization in the IS-enhanced group. Conclusion: Compared to traditional pulmonary function training, IS-enhanced training can significantly accelerate the improvement of pulmonary function testing parameters, shorten the preoperative pulmonary function training time, reduce the incidence of postoperative pulmonary tension complications, and accelerate postoperative rehabilitation.

Kidney-Type Glutaminase Inhibitor Hexylselen Selectively Kills Cancer Cells via a Three-Pronged Mechanism.

Tumor metabolism has been deeply investigated for cancer therapeutics. Here, we demonstrate that glutamine deficiency alone could not completely inhibit cancer cell growth and that many potent kidney-type glutaminase (KGA) inhibitors did not show satisfying in vivo efficacy. The potent KGA allosteric inhibitor, CB-839, resulted in up to 80% growth inhibition of all tested cell lines, whereas Hexylselen (CPD-3B), a KGA/glutamate dehydrogenase (GDH) inhibitor, showed essentially no toxicity to normal cells up to a 10 µM concentration and could completely inhibit the growth of many aggressive cell lines. Further analyses showed that CPD-3B targets not only KGA and GDH but also thioredoxin reductase (TrxR) and amidotransferase (GatCAB), which results in corresponding regulation of Akt/Erk/caspase-9 signaling pathways. In an aggressive liver cancer xenograft model, CPD-3B significantly reduced tumor size, caused massive tumor tissue damage, and prolonged survival rate. These provide important information for furthering the drug design of an effective anticancer KGA allosteric inhibitor.