[The efficacy of chemotherapy re-challenge in third-line setting for metastatic colorectal cancer patients: a real-world study].

Objective: To explore the efficacy of chemotherapy re-challenge in the third-line setting for patients with metastatic colorectal cancer (mCRC) in the real world. Methods: The clinicopathological data, treatment information, recent treatment efficacy, adverse events and survival data of mCRC patients who had disease progression after treatment with oxaliplatin-based and/or irinotecan-based chemotherapy and received third-line chemotherapy re-challenge from January 2013 to December 2020 at Tianjin Medical University Cancer Institute and Hospital were retrospectively collected. Survival curves were plotted with the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the prognostic factors. Results: A total of 95 mCRC patients were included. Among them, 32 patients (33.7%) received chemotherapy alone and 63 patients (66.3%) received chemotherapy combined with targeted drugs. Eighty-three patients were treated with dual-drug chemotherapy (87.4%), including oxaliplatin re-challenge in 35 patients and irinotecan re-challenge in 48 patients. The remaining 12 patients were treated with triplet chemotherapy regimens (12.6%). Among them, as 5 patients had sequential application of oxaliplatin and irinotecan in front-line treatments, their third-line therapy re-challenged both oxaliplatin and irinotecan; 7 patients only had oxaliplatin prescription before, and these patients re-challenged oxaliplatin in the third-line treatment. The overall response rate (ORR) and disease control rate (DCR) reached 8.6% (8/93) and 61.3% (57/93), respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.9 months and 13.0 months, respectively. The most common adverse events were leukopenia (34.7%) and neutropenia (34.7%), followed by gastrointestinal adverse reactions such as nausea (32.6%) and vomiting (31.6%). Grade 3-4 adverse events were mostly hematological toxicity. Cox multivariate analysis showed that gender (HR=1.609, 95% CI: 1.016-2.548) and the PFS of front-line treatments (HR=0.598, 95% CI: 0.378-0.947) were independent prognostic factors. Conclusion: The results suggested that it is safe and effective for mCRC patients to choose third-line chemotherapy re-challenge, especially for patients with a PFS of more than one year in front-line treatments.

[Effect of oral administration of branched-chain amino acids supplementation on the mortality of patients with hepatocellular carcinoma: a meta-analysis].

Objective: To investigate the effect of oral administration of branched-chain amino acids (BCAA) supplementation on the mortality of patients with hepatocellular carcinoma (HCC) after treatment. Methods: Computer searching of PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Biomedical Literature Database was conducted to search for clinical controlled trials and randomized controlled trials (RCTs) on the effect of oral administration of BCAA on the mortality of patients with HCC. The retrieval time limit was from the time of the establishment of each database to December 30, 2019. Two researchers independently screened the literature and extracted the data. Another researcher assessed the risk of bias in the included studies and then used RevMan 5.3 software for meta-analysis. Results: A total of 14 studies were included with 1 179 patients. The overall results showed that oral administration of BCAA had no significant effect on the mortality of HCC patients at 1 year after treatment (RR=0.85, 95%CI:0.68-1.06, P=0.16), while the mortalities of patients at 3 years (RR=0.73, 95%CI: 0.61-0.88, P=0.000 7) and 5 years (RR=0.57, 95%CI:0.34-0.96, P=0.03) after treatment were significantly lower than those of the control group. The subgroup analysis showed that for radiofrequency ablation (RFA) patients, there was no significant difference in 1-year mortality between the BCAA group and the control group (RR=0.96, 95%CI:0.14-6.5, P=0.97), while 3-year mortality was significantly reduced (RR=0.59, 95%CI:0.43-0.81, P=0.001); for hepatectomy patients, there was no significant differences in 1 -and 3-year mortality between the two groups (RR=0.90, 95%CI:0.44-1.88, P=0.79; RR=0.97, 95%CI:0.71-1.33, P=0.85, respectively). In addition, as for albumin levels, BCAA supplementation significantly increased albumin levels without considering the treatment of HCC (SD=0.45, 95%CI: 0.29-0.90; P=0.000 1), but had no significant effect on hepatectomy patients (SD=0, 95%CI: -0.41-0.41, P=0.99). Conclusion: BCAA supplementation might improve liver reserve function and long-term prognosis of HCC patients, which was related to the surgical method. Supplementing BCAA reduced the long-term mortality of RFA patients, but had no significant effect on hepatectomy patients.

Cathepsin S in the spinal microglia contributes to remifentanil-induced hyperalgesia in rats.

Cysteine protease Cathepsin S (CatS) expressed by spinal microglia has been shown to play a critical role in nerve injury and inflammation-induced chronic pain. However, whether microglial CatS contributes to remifentanil-induced acute hyperalgesia remains unstudied. In the present study, intravenous remifentanil infusion induced a significant increase in the expression of premature and mature form of CatS in the activated microglia in the spinal cord. Spinal delivery of irreversible CatS inhibitor LHVS reduced hyperalgesia, attenuated activation of spinal microglia and blocked phosphorylation of NMDA receptor NR1 subunit induced by remifentanil. Furthermore, inhibition of microglia by minocycline effectively suppressed remifentanil-induced hyperalgesia, as well as CatS upregulation. In addition, remifentanil infusion also induced an increase in reactive oxygen species (ROS) levels in spinal neurons. Systemic administration of ROS scavenger PBN was sufficient to suppress remifentanil-induced painful hypersensitivity. Removal of ROS by PBN prevented upregulation of mature CatS in spinal microglia. However, increased protein level of premature form of CatS was not affected by PBN. Altogether, our findings demonstrate that neuronal ROS promote maturation of microglial CatS which facilitates activation of NMDA in the spinal dorsal horn. Therefore, such mechanism is involved in neuron-microglia positive feedback and contributes to remifentanil-induced hyperalgesia.

Pharmacokinetics of 5-fluorouracil and cyclophosphamide in depression rats.

OBJECTIVES: Efficacy and toxicity of the drug are mainly determined by physicochemical properties and pharmacological effects of its own. In addition, they are also affected by other factors, such as gender, age, genetic character, pathophysiological status, mood states and so on. The paper aims to study whether mood disorder alters drug metabolism process through the pharmacokinetic research on some clinically important anticancer drugs in depression model rats. MATERIALS AND METHODS: The depression model rats were built by exposing to chronic unpredicted mild stresses (CUMS) for 8 weeks. 36 female Sprague-Dawley (SD) rats were randomized into model group and control group. In each group, 18 rats were randomized into 2 subgroups: 5-fluorouracil (5-FU) subgroup and cyclophosphamide (CP) subgroup which were given a certain doses of 5-FU and CP. The blood samples were collected at different time points and plasma drug concentration were respectively assayed by high performance liquid chromatography (HPLC) for 5-FU and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for CP. Pharmacokinetic parameters were processed with DAS software. RESULTS: There were significant differences in the pharmacokinetic parameters of 5-FU and CP between in depression model rats group and in the normal control group (p < 0.05), except t1/2alpha (p > 0.05) for CP pharmacokinetics in depression model rats group and in the normal control rats group, with the value of those was 0.07 and 0.09 h. CONCLUSIONS: Depression mood disorder might alter drug metabolism process.

Enzymatic synthesis oF L-tryptophan from D,L-2-amino-delta2-thiazoline-4-carboxylic acid and indole by Pseudomonas sp. TS1138 L-2-amino-delta2-thiazoline-4-carboxylic acid hydrolase, S-carbamyl-L-cysteine amidohydrolase, and Escherichia coli L-tryptophanase.

L-Tryptophan (L-Trp) is an essential amino acid. It is widely used in medical, health and food products, so a low-cost supply is needed. There are 4 methods for L-Trp production: chemical synthesis, extraction, enzymatic synthesis, and fermentation. In this study, we produced a recombinant bacterial strain pET-tnaA of Escherichia coli which has the L-tryptophanase gene. Using the pET-tnaA E. coli and the strain TS1138 of Pseudomonas sp., a one-pot enzymatic synthesis of L-Trp was developed. Pseudomonas sp. TS1138 was added to a solution of D,L-2-amino-delta2-thiazoline-4-carboxylic acid (DL-ATC) to convert it to L-cysteine (L-Cys). After concentration, E. coli BL21 (DE 3) cells including plasmid pET-tnaA, indole, and pyridoxal 5'-phosphate were added. At the optimum conditions, the conversion rates of DL-ATC and L-Cys were 95.4% and 92.1%, respectively. After purifying using macroporous resin S8 and NKA-II, 10.32 g of L-Trp of 98.3% purity was obtained. This study established methods for one-pot enzymatic synthesis and separation of L-Trp. This method of producing L-Trp is more environmentally sound than methods using chemical synthesis, and it lays the foundations for industrial production of L-Trp from DL-ATC and indole.

Impact of depression mood disorder on the adverse drug reaction incidence rate of anticancer drugs in cancer patients.

The aim of this study was to explore the impact of depression mood disorder on the incidence of adverse drug reactions of anticancer drugs in cancer patients. The Hamilton Depression Scale 17 was used to evaluate the depression mood disorder level in 73 cancer patients before chemotherapy. Pharmacists monitored adverse drug reactions during the chemotherapy period. The relationship between depression mood disorder level and the incidence of adverse drug reactions was analysed. The frequency and extent of total adverse drug reactions were not related to depression mood disorder level. The frequency and extent of subjectively experienced adverse drug reactions such as anorexia, nausea and fatigue were related to depression mood disorder level. In conclusion, psychological support and intervention should be provided to cancer patients in order to improve patient adherence and cancer chemotherapy effectiveness, and to decrease the incidence of adverse drug reactions.

Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo.

To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2' linkers. With an N-methylamide at P3', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3'-P4' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC(50) values of