A multiplex liquid chromatography tandem mass spectrometry method for the quantification of seven therapeutic monoclonal antibodies: Application for adalimumab therapeutic drug monitoring in patients with Crohn's disease.

Anal Chim Acta. 2019 Aug 27;1067:63-70

Authors: Willeman T, Jourdil JF, Gautier-Veyret E, Bonaz B, Stanke-Labesque F

Abstract
The use of therapeutic monoclonal antibodies (mAbs) is steadily increasing. Previous studies have reported the clinical interest of mAb therapeutic-drug monitoring (TDM), including that of adalimumab, for patients with Crohn's disease (CD). Proof of concept mAb-quantification studies by liquid chromatography mass spectrometry (LC-MS/MS) have been published, but a specific and reliable routine-suited multiplex quantification method is still needed to facilitate mAb TDM. We describe an electrospray ionization LC-MS/MS method for the simultaneous quantification of seven mAbs (adalimumab, cetuximab, infliximab, rituximab, secukinumab, tocilizumab, and trastuzumab) in human plasma. Sample preparation was performed using protein-G purification and trypsin digestion to obtain proteotypic peptides. We retrospectively measured the adalimumab concentration in 65 plasma samples from 56 CD patients and determined the adalimumab therapeutic cut-off concentration associated with biological remission. Calibration curves were linear from 1 to 100 μg mL-1, except for rituximab (5-100 μg mL-1). This method was reproducible, repeatable, and accurate (coefficient of variation and bias < 20%), with no cross contamination. Adalimumab concentrations were significantly higher (p = 0.0198) for patients with biological remission (median: 11.3 μg mL-1 [4.6; 18.3]) than that for patients without a biological response (9.5 μg mL-1 [3.94;17.0]). An adalimumab cut-off concentration of 8.0 μg mL-1 correctly discriminated patients with or without biological remission (sensitivity: 74.1%, specificity: 57.9%). This validated LC-MS/MS routine-suited method is the first allowing simultaneous quantification of up to seven mAbs acting against different pharmacological targets. It opens the field of TDM to numerous mAbs.

PMID: 31047150 [PubMed - indexed for MEDLINE]

Harmonization of urine albumin/creatinine ratio (ACR) results: a study based on an external quality assessment program in Polish laboratories.

Clin Chem Lab Med. 2018 09 25;56(10):1728-1733

Authors: Ćwiklińska A, Dąbrowska H, Kowalski R, Kuchta A, Kortas-Stempak B, Fijałkowska A, Bednarczuk G, Jankowski M

PMID: 29750641 [PubMed - indexed for MEDLINE]

Fetal auditory evoked responses to onset of amplitude modulated sounds. A fetal magnetoencephalography (fMEG) study.

Hear Res. 2018 06;363:70-77

Authors: Draganova R, Schollbach A, Schleger F, Braendle J, Brucker S, Abele H, Kagan KO, Wallwiener D, Fritsche A, Eswaran H, Preissl H

Abstract
The human fetal auditory system is functional around the 25th week of gestational age when the thalamocortical connections are established. Fetal magnetoencephalography (fMEG) provides evidence for fetal auditory brain responses to pure tones and syllables. Fifty-five pregnant women between 31 and 40 weeks of gestation were included in the study. Fetal MEG was recorded during the presentation of an amplitude modulated tone (AM) with a carrier frequency of 500 Hz to the maternal abdomen modulated by low modulation rates (MRs) - 2/s and 4/s, middle MR - 8/s and high MRs - 27/s, 42/s, 78/s and 91/s. The aim was to determine whether the fetal brain responds differently to envelope slopes and intensity change at the onset of the AM sounds. A significant decrease of the response latencies of transient event-related responses (ERR) to high and middle MRs in comparison to the low MRs was observed. The highest fetal response rate was achieved by modulation rates of 2/s, 4/s and 27/s (70%, 57%, and 86%, respectively). Additionally, a maturation effect of the ERR (response latency vs. gestational age) was observed only for 4/s MR. The significant difference between the response latencies to low, middle, and high MRs suggests that still before birth the fetal brain processes the sound slopes at the onset in different integration time-windows, depending on the time for the intensity increase or stimulus power density at the onset, which is a prerequisite for language acquisition.

PMID: 29534830 [PubMed - indexed for MEDLINE]

Genotype-guided antiplatelet therapy compared with conventional therapy for patients with acute coronary syndromes: a systematic review and meta-analysis.

Biomarkers. 2019 Jun 19;:1-24

Authors: Zheng L, Yang C, Xiang L, Hao Z

Abstract
Objective: To evaluate whether genotype-guided antiplatelet therapy reduces the rates of cardiovascular events and bleeding events in patients with acute coronary syndrome (ACS). Methods: We systematically searched Pubmed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) (searched in September 2018) for controlled studies evaluating genotype-guided antiplatelet therapy in ACS with percutaneous coronary intervention (PCI) or without PCI. The primary endpoint was a composite of death, myocardial infarction (MI), stroke, targeted vessel revascularization and/or major bleeding. Results: A total of five studies involving 2900 patients were included. Compared with the conventional group, the genotype-guided group had a decreased risk of primary composite outcomes (RR= 0.54; 95% CI: 0.41-0.72; I2 = 30%), death (RR =0.54; 95% CI: 0.32-0.94; I2 = 21%), MI (RR =0.52; 95% CI: 0.31-0.88; I2 = 49%), targeted vessel revascularization (RR =0.59; 95% CI: 0.35-0.98; I2 = 0%), but not for stroke (RR =0.53; 95% CI: 0.22-1.24; I2 = 0%) and bleeding events (RR =0.80; 95% CI: 0.51-1.25; I2 = 33%). Conclusions: Genotype-guided strategies could reduce the rates of cardiovascular events without increasing bleeding events compared with conventional treatment in ACS. Future multi-center genotype-based RCTs are required to confirm these findings.

PMID: 31215825 [PubMed - as supplied by publisher]

Personalized medicine in breast cancer: pharmacogenomics approaches.

Pharmgenomics Pers Med. 2019;12:59-73

Authors: Jeibouei S, Akbari ME, Kalbasi A, Aref AR, Ajoudanian M, Rezvani A, Zali H

Abstract
Breast cancer is the fifth cause of cancer death among women worldwide and represents a global health concern due to the lack of effective therapeutic regimens that could be applied to all disease groups. Nowadays, strategies based on pharmacogenomics constitute novel approaches that minimize toxicity while maximizing drug efficacy; this being of high importance in the oncology setting. Besides, genetic profiling of malignant tumors can lead to the development of targeted therapies to be included in effective drug regimens. Advances in molecular diagnostics have revealed that breast cancer is a multifaceted disease, characterized by inter-tumoral and intra-tumoral heterogeneity and, unlike the past, molecular classifications based on the expression of individual biomarkers have led to devising novel therapeutic strategies that improve patient survival. In this review, we report and discuss the molecular classification of breast cancer subtypes, the heterogeneity resource, and the advantages and disadvantages of current drug regimens with consideration of pharmacogenomics in response and resistance to treatment.

PMID: 31213877 [PubMed]

Health, pleasure, and fullness: changing mindset affects brain responses and portion size selection in adults with overweight and obesity.

Int J Obes (Lond). 2019 Jun 18;:

Authors: Veit R, Horstman LI, Hege MA, Heni M, Rogers PJ, Brunstrom JM, Fritsche A, Preissl H, Kullmann S

Abstract
BACKGROUND: Increased portion size is an essential contributor to the current obesity epidemic. The decision of how much to eat before a meal begins (i.e. pre-meal planning), and the attention assigned to this task, plays a vital role in our portion control.
OBJECTIVE: We investigated whether pre-meal planning can be influenced by a shift in mindset in individuals with overweight and obesity in order to influence portion size selection and brain activity.
DESIGN: We investigated the neural underpinnings of pre-meal planning in 36 adults of different weight groups (BMI < 25 kg/m2 and BMI ≥ 25 kg/m2) by means of functional magnetic resonance imaging. To examine the important role of attentional focus, participants were instructed to focus their mindset on the health effects of food, expected pleasure, or their intention to stay full until dinnertime, while choosing their portion size for lunch.
RESULTS: We observed that participants of all weight groups reduced their portion size when adopting a health mindset, which was accompanied by enhanced activation of the self-control network (i.e. left prefrontal cortex). Fullness and pleasure mindsets resulted in contrasting reward responses in individuals with overweight and obesity compared to normal-weight individuals. Under the pleasure mindset, persons with overweight and obesity showed heightened activity in parts of the taste cortex (i.e. right frontal operculum), while the fullness mindset caused reduced activation in the ventral striatum, an important component of the reward system. Moreover, participants with overweight and obesity did not modify their behaviour under the pleasure mindset and selected larger portions than the normal-weight group.
CONCLUSIONS: We were able to identify specific brain response patterns as participants made a final choice of a portion size. The results demonstrate that different brain responses and behaviours during pre-meal planning can inform the development of effective strategies for healthy weight management.

PMID: 31213656 [PubMed - as supplied by publisher]

Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens.

J Transl Med. 2018 07 17;16(1):197

Authors: Chen P, Zhu KW, Zhang DY, Yan H, Liu H, Liu YL, Cao S, Zhou G, Zeng H, Chen SP, Zhao XL, Yang J, Chen XP

Abstract
BACKGROUNDS: UDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver.
METHODS: UGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated.
RESULTS: After one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379-0.737, P = 1.7 × 10-4) and better overall survival (HR = 0.787, 95% CI 0.627-0.990, P = 0.040) as compared with homozygotes for both polymorphisms.
CONCLUSION: Our results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.

PMID: 30016963 [PubMed - indexed for MEDLINE]

Association of genetic polymorphisms in genes involved in Ara-C and dNTP metabolism pathway with chemosensitivity and prognosis of adult acute myeloid leukemia (AML).

J Transl Med. 2018 04 10;16(1):90

Authors: Zhu KW, Chen P, Zhang DY, Yan H, Liu H, Cen LN, Liu YL, Cao S, Zhou G, Zeng H, Chen SP, Zhao XL, Chen XP

Abstract
BACKGROUND: Cytarabine arabinoside (Ara-C) has been the core of chemotherapy for adult acute myeloid leukemia (AML). Ara-C undergoes a three-step phosphorylation into the active metabolite Ara-C triphosphosphate (ara-CTP). Several enzymes are involved directly or indirectly in either the formation or detoxification of ara-CTP.
METHODS: A total of 12 eQTL (expression Quantitative Trait Loci) single nucleotide polymorphisms (SNPs) or tag SNPs in 7 genes including CMPK1, NME1, NME2, RRM1, RRM2, SAMHD1 and E2F1 were genotyped in 361 Chinese non-M3 AML patients by using the Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, relapse-free survival (RFS) and overall survival (OS) were analyzed.
RESULTS: Three SNPs were observed to be associated increased risk of chemoresistance indicated by CR rate (NME2 rs3744660, E2F1 rs3213150, and RRM2 rs1130609), among which two (rs3744660 and rs1130609) were eQTL. Combined genotypes based on E2F1 rs3213150 and RRM2 rs1130609 polymorphisms further increased the risk of non-CR. The SAMHD1 eQTL polymorphism rs6102991 showed decreased risk of non-CR marginally (P = 0.055). Three SNPs (NME1 rs3760468 and rs2302254, and NME2 rs3744660) were associated with worse RFS, and the RRM2 rs1130609 polymorphism was marginally associated with worse RFS (P = 0.085) and OS (P = 0.080). Three SNPs (NME1 rs3760468, NME2 rs3744660, and RRM1 rs183484) were associated with worse OS in AML patients.
CONCLUSION: Data from our study demonstrated that SNPs in Ara-C and dNTP metabolic pathway predict chemosensitivity and prognosis of AML patients in China.

PMID: 29631596 [PubMed - indexed for MEDLINE]

Tamoxifen Pharmacogenetics and Metabolism: The Same Is Not the Same.

J Clin Oncol. 2019 Jun 18;:JCO1900507

Authors: Brauch H, Schroth W, Mürdter T, Schwab M

PMID: 31211600 [PubMed - as supplied by publisher]

Predicting (side) effects for patients with inflammatory bowel disease: The promise of pharmacogenetics.

World J Gastroenterol. 2019 Jun 07;25(21):2539-2548

Authors: Voskuil MD, Bangma A, Weersma RK, Festen EAM

Abstract
Inflammatory bowel disease (IBD) is a chronic and heterogeneous intestinal inflammatory disorder. The medical management of IBD aims for long-lasting disease remission to prevent complications and disease progression. Early introduction of immunosuppression forms the mainstay of medical IBD management. Large inter-individual variability in drug responses, in terms of both efficacy and toxicity, leads to high rates of therapeutic failure in the management of IBD. Better patient stratification is needed to maximize patient benefit and minimize the harm caused by adverse events. Pre-treatment pharmacogenetic testing has the potential to optimize drug selection and dose, and to minimize harm caused by adverse drug reactions. In addition, optimizing the use of cheap conventional drugs, and avoiding expensive ineffective drugs, will lead to a significant reduction in costs. Genetic variation in both TPMT and NUDT15, genes involved in thiopurine metabolism, is associated to an increased risk of thiopurine-induced myelosuppression. Moreover, specific HLA haplotypes confer risk to thiopurine-induced pancreatitis and to immunogenicity to tumor necrosis factor-antagonists, respectively. Falling costs and increased availability of genetic tests allow for the incorporation of pre-treatment genetic tests into clinical IBD management guidelines. In this paper, we review clinically useful pharmacogenetic associations for individualized treatment of patients with IBD and discuss the path from identification of a predictive pharmacogenetic marker to implementation into IBD clinical care.

PMID: 31210708 [PubMed - in process]

Value of a Hypothetical Pharmacogenomic Test for the Diagnosis of Statin-Induced Myopathy in Patients at High Cardiovascular Risk.

Mol Diagn Ther. 2018 12;22(6):641-652

Authors: Mitchell D, Guertin JR, LeLorier J

Abstract
We recently conducted two economic evaluations of a hypothetical pharmacogenomic test for statin-induced myopathy (SIM) in patients at high cardiovascular risk. Although the models differed in modeling technique and data inputs, both yielded similar results. We believe our approach to assessing the economic value of a diagnostic test was highly advantageous as it characterized the complete range of false-negative and false-positive test outcomes. We used a broad interpretation of test parameters that reflected physician and patient behavioral responses to the test results and accounted for patient adherence to treatment. Both economic evaluations indicated that a highly accurate pharmacogenomic test for SIM would provide a positive incremental net monetary benefit (INMB) for a provincial payer in Canada. However, the value of the test would depend on its ability to accurately diagnose patients when they experience musculoskeletal pain symptoms and guide patients with a test result indicating no SIM to adhere to treatment. Interestingly, our results indicated that a highly inaccurate test would still yield a positive INMB. We found this surprising result was driven by the imbalance of the risk of cardiovascular events outweighing the risk of rhabdomyolysis in patients at high cardiovascular risk. A highly accurate pharmacogenomic test for SIM in patients at high cardiovascular risk would provide economic value for payers. However, the economic and clinical value of the test would depend on the credibility of the test results and their success in influencing patients without SIM to adhere to therapy.

PMID: 30218425 [PubMed - indexed for MEDLINE]

Pharmacokinetics of Meropenem in Burn Patients with Infections Caused by Gram Negative Bacteria: Are We Getting Close to the Right Treatment?

J Glob Antimicrob Resist. 2019 Jun 14;:

Authors: Corcione S, D'Avolio A, Corgiat Loia R, Pensa A, Segala FV, De Nicolò A, Fatiguso G, Romeo M, Di Perri G, Stella M, De Rosa FG

Abstract
BACKGROUND: Infections caused by multi drug resistant (MDR) gram negative bacteria are associated with high mortality. A relevant concern is the efficacy of antibiotic therapies in burn patients in which the pathophysiological changes strongly influence the pharmacokinetic (PK) parameters.
OBJECTIVE: Aim of the study was to describe the PK parameters of meropenem in a population of burn patients.
METHODS: Blood samples were collected immediately before (T0), and after 2 and 5 hours after intravenous drug administration. Plasma meropenem concentrations were determined using an ultra performance liquid chromatography-photodiode array method.
RESULT: Seventeen burn patients were enrolled in the study. Thirteen patients (76%) were treated with meropenem for P. Aeruginosa and A. Baumannii isolated from blood or wounds. The mean Cmax, Cmin, AUC0-24, half-life (T1/2), clearance (CL) and volume distribution (Vd) were: 28.9 mg/L, 3.7 mg/L, 109.2 mg/Lh, 2.4 h, 17.1 L/h, 47.6 L respectively. Six patients (35%) achieved a Cmin ≥ 3.3 mg/L and seven patients (41%) achieved a Cmax ≥ 28,4 mg/L, while 9 patients (53%) achieved an AUC0-24 of 226 mg/Lh. Given a MIC of 0.5 mg/L, all patients satisfied the target AUC/MIC of >125, but when the MIC rises up to 2 mg/L (ECOFF), only 5 patients reached the desired AUC/MIC. Regarding ft > MIC of 2 mg/L with infusion time of 2 h, 13 patients (76%) achieved the PK target (>75%).
CONCLUSION: These data suggest that a combined 2 h infusion with a higher dosage of meropenem, including a loading dose, may be successful to achieve effective PK parameters.

PMID: 31207380 [PubMed - as supplied by publisher]

Mebendazole induces apoptosis via C-MYC inactivation in malignant ascites cell line (AGP01).

Toxicol In Vitro. 2019 Jun 14;:

Authors: Pinto LC, Mesquita FP, Soares BM, da Silva EL, Puty B, de Oliveira EHC, Burbano RR, Montenegro RC

Abstract
The objective of study was examine the role of MBZ on Malignant Ascites cells and the involvement of C-MYC. Comet assay was used to assess the genotoxic effects of MBZ in AGP01 cells and human lymphocytes; differential staining by ethidium bromide and acridine orange, caspase 3/7 and flow cytometry assay was done to access the mechanisms of apoptosis and cell cycle analysis of MBZ in AGP01 cells. C-MYC amplification, C-MYC mRNA and C-MYC protein expression were evaluated by FISH, RT-qPCR and Western blotting, respectively. In addition, cytotoxicity of MBZ was evaluated in AGP01 and AGP01 shRNA MYC by MTT. MBZ significantly increased the damage index and no produced in human lymphocytes. MBZ caused remarkable cell cycle arrest in G0/G1 and G2/M phases at 0.5 μM and 1.0 μM, respectively and induced significantly apoptosis in higher concentrations. Additionally, MBZ (0.5 μM and 1.0 μM) increased caspase 3 and 7 activities. MBZ decreased signals, C-MYC mRNA and C-MYC protein expression in AGP01 cells. MBZ induced lower cell viability in AGP01 cells compared AGP01 shRNA MYC in the same concentration. Therefore, our results show the evidence of C-MYC gene as one of the pathways by which MBZ induces cell death in gastric cancer cells.

PMID: 31207347 [PubMed - as supplied by publisher]

Calling star alleles with Stargazer in 28 pharmacogenes with whole genome sequences.

Clin Pharmacol Ther. 2019 Jun 17;:

Authors: Lee SB, Wheeler MM, Thummel KE, Nickerson DA

Abstract
Variation in the enzymatic activity of pharmacogenes is defined by star alleles (haplotypes) comprised of single nucleotide variants, small insertion-deletions, and large structural variants. We recently developed Stargazer, a next-generation sequencing-based tool to call star alleles for the clinically important CYP2D6 gene. Here, we present the utility of extending Stargazer to call star alleles for 28 pharmacogenes using whole genome sequencing (WGS) data. We applied Stargazer to WGS data from 70 ethnically diverse samples from the Genetic Testing Reference Materials Coordination Program (GeT-RM). These reference samples were extensively characterized by GeT-RM using multiple pharmacogenetic testing assays. In all 28 genes, Stargazer recalled 100% of star alleles (N=92) present in GeT-RM's consensus genotypes (N=1559). Stargazer also detected star alleles not previously reported by GeT-RM including complex structural variants. Our results demonstrate that combining WGS data and Stargazer enables automated, accurate, and comprehensive genotyping of pharmacogenes in the human genome. This article is protected by copyright. All rights reserved.

PMID: 31206625 [PubMed - as supplied by publisher]

Increased versus Stable Dose of Inhaled Corticosteroids for Asthma Exacerbations: A Systematic Review and Meta-analysis.

Clin Exp Allergy. 2019 Jun 17;:

Authors: Zhang Y, He J, Yuan Y, Faramand A, Fang F, Ji H

Abstract
BACKGROUND: Increasing the dose of inhaled corticosteroids (ICS) is commonly used at early signs of loss of asthma control. However, the potential benefits and harms of this strategy remain unclear. We performed a systematic review and meta-analysis to compare increased dose with stable dose of ICS among adults and children with asthma.
METHODS: We searched Medline, EMBASE, and Cochrane Central Register of Controlled Trials from inception to August 02, 2018. Randomized clinical trials comparing increased doses vs stable doses of ICS for home management of asthma exacerbations in adults or children were included.
RESULTS: The analyses included 8 trials totaling 3866 patients. Four trials were judged as low risk of bias, three were unclear risk, and one was ranked as high risk. Increased dose of ICS was associated with a significantly reduced risk of treatment failure compared with stable dose (OR 0.82, 95% CI 0.70-0.97, I2=6%; 314 (281 to 351) vs 358 events per 1,000 patients; moderate-quality evidence). There was no significant difference in unscheduled physician visits or hospital admission between increased or stable dose of ICS. However, increased dose of ICS increased the risk of non-serious adverse events (OR 3.50, 95% CI 1.93-6.35, I2=0%) but not serious adverse events.
CONCLUSIONS: Current evidence of moderate quality supports increasing the dose of ICS as part of a self-initiated action plan to reduce risk of requiring a course of systemic corticosteroids in people with an asthma exacerbation. However we did not find evidence for an impact on hospital admissions or unscheduled physician visits, and increased ICS dose increased risk of non-serious adverse events. This article is protected by copyright. All rights reserved.

PMID: 31206220 [PubMed - as supplied by publisher]

The Fibroblast TIAM2 Promotes Lung Cancer Cell Invasion and Metastasis.

J Cancer. 2019;10(8):1879-1889

Authors: Li S, Ou Y, Liu S, Yin J, Zhuo W, Huang M, Zhu T, Zhang W, Zhou H, Liu Z

Abstract
Purpose: TIAM2 (T-cell lymphoma invasion and metastasis 2), a RAC1 guanine nucleotide exchange factor, plays crucial roles in human cancer cells. Its homolog, TIAM1, has been reported to promote the migration and invasion of cancer cells through regulating the functions of cancer associated fibroblasts (CAFs). However, the functions of TIAM2 in CAFs have not been investigated. In this study, we explored how fibroblast TIAM2 influences the migration and invasion of lung cancer cells. Methods: We cultured primary lung CAFs and adjacent normal lung fibroblasts (NFs) from 12 non-small cell lung cancer (NSCLC) patients. RT-PCR and western blot were used to compare TIAM2 levels between CAFs and NFs. Two co-culture systems were designed, in which cancer cells were directly co-cultured with fibroblasts and indirectly co-cultured with conditional medium (CM) from fibroblasts. Subsequently, the wound healing and transwell tests were conducted to assess the migration and invasion ability of fibroblasts and co-cultured cancer cells. Finally, cytokine antibody arrays were used to screen differentially secreted cytokines in the CM. Results: The expression levels of TIAM2 were significantly higher in CAFs than NFs, and TIAM2-silenced fibroblasts showed decreased migration and invasion ability. In the direct co-culture system, the migration and invasion of cancer cells were retarded when co-culturing with TIAM2-silenced fibroblasts, and the expression levels of EMT-related genes also changed in cancer cells. Decreased migration and invasion of cancer cells were also observed when culturing with the CM from TIAM2-silenced fibroblasts. In addition, the cytokine antibody arrays revealed that Osteoprotegerin (OPG) was significantly decreased in the CM of TIAM2-silenced fibroblasts. This result suggested that OPG might be one of the main cytokines contributing to the migration and invasion of cancer cells in co-culture systems. Conclusion: Our results suggest that fibroblast TIAM2 promotes the invasion and migration of lung cancer cell, and OPG might be one of the main cytokines contributing to this pro-cancer process.

PMID: 31205545 [PubMed]

The Prospective Value of Dopamine Receptors on Bio-Behavior of Tumor.

J Cancer. 2019;10(7):1622-1632

Authors: Wang X, Wang ZB, Luo C, Mao XY, Li X, Yin JY, Zhang W, Zhou HH, Liu ZQ

Abstract
Dopamine receptors are belong to the family of G protein-coupled receptor. There are five types of dopamine receptor (DR), including DRD1, DRD2, DRD3, DRD4, and DRD5, which are divided into two major groups: the D1-like receptors (DRD1 and DRD5), and the D2-like receptors (DRD2, DRD3, and DRD4). Dopamine receptors are involved in all of the physiological functions of dopamine, including the autonomic movement, emotion, hormonal regulation, dopamine-induced immune effects, and tumor behavior, and so on. Increasing evidence shows that dopamine receptors are associated with the regulation of tumor behavior, such as tumor cell death, proliferation, invasion, and migration. Recently, some studies showed that dopamine receptors could regulate several ways of death of the tumor cell, including apoptosis, autophagy-induced death, and ferroptosis, which cannot only directly affect tumor behavior, but also limit tumor progress via activating tumor immunity. In this review, we focus mainly on the function of the dopamine receptor on Bio-behavior of tumor as a potential therapeutic target.

PMID: 31205518 [PubMed]

Intensive first-line FIr-C/FOx-C association of triplet chemotherapy plus cetuximab in RAS wild-type metastatic colorectal cancer patients: preliminary phase II data and prediction of individual limiting toxicity syndromes by pharmacogenomic biomarkers.

Ther Adv Med Oncol. 2019;11:1758835919846421

Authors: Bruera G, Massacese S, Pepe F, Malapelle U, Dal Mas A, Ciacco E, Calvisi G, Troncone G, Simmaco M, Ricevuto E

Abstract
Background: Intensive triplet chemotherapy/bevacizumab significantly increased metastatic colorectal cancer (MCRC) outcome. This phase II study investigated the safety/activity of FIr-C/FOx-C triplet/cetuximab (CET) in first-line RAS wild-type and the prediction of individual limiting toxicity syndromes (LTS) by pharmacogenomic biomarkers.
Methods: A Simon two-step design was used: p0 70%, p1 85%, power 80%, α5%, β20%; projected objective response rate (ORR) I step 14/19. FIr-C/FOx-C: 5-fluorouracil (5-FU) 12h-timed flat infusion 900 mg/m2 d1-2, 8-9, 15-16, 22-23; irinotecan (CPT-11) 160 mg/m2 d1 and 15, oxaliplatin 80 mg/m2 d8 and 22; CET 400mg/m2 then 250 mg/m2 d1, 8, 15, 22; every 28 days. Toxicity, and individual LTS were evaluated, compared by a Chi-square test; and activity/efficacy by log-rank. 5-FU/CPT-11 pharmacogenomic biomarkers, 5-FU degradation rate (5-FUDR), single nucleotide polymorphisms (SNPs) ABCB1, CYP3A4, DYPD, UGT1A1 were evaluated in patients with LTS and at a recommended dose.
Results: A total of 29 patients <75 years, with a primary/intermediate Cumulative Index Rating Scale were enrolled; the median age was 59 years; there were 7 young-elderly (yE; 24%). Recommended CPT-11/5-FU doses were 120/750 mg/m2. In the intent-to-treat analysis, the ORR was 58.6%. The primary endpoint was met in patients who received the planned three treatment cycles: the objective response (OR) was 14/18 (78%). At a median follow up of 18 months, progression-free survival (PFS) was 12, and overall survival (OS) was 23 months. At the recommended doses (received dose intensity >80%), grade 3-4 toxicities were: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%; LTS 19 (65.5%), with 83% in yE patients. LTS prevalently multiple (ms) versus single site were 59% versus 7% (p = 0.006). The prevalence of reduced FUDR was 56%, SNPs CYP3A4 22%, UGT1A1 71%, and of >2 positive pharmacogenomics biomarkers was 78%, prevalently reported in patients who developed gastrointestinal LTS.
Conclusions: FIr-C/FOx-C is highly active and tolerable at recommended doses in non-elderly RAS wild-type MCRC patients. LTS provided an evaluation of the toxicity burden in individual patients. Reduced FUDR, CYP3A4, and UGT1A1 SNPs may predict individual LTS-ms in patients at risk of limiting gastrointestinal toxicity.
Trial registration: The trial was registered at Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2009-016793-32.

PMID: 31205502 [PubMed]

Identification of Novel Pathways in Idelalisib Metabolism and Bioactivation.

Chem Res Toxicol. 2018 07 16;31(7):548-555

Authors: Zhu J, Wang P, Shehu AI, Lu J, Bi H, Ma X

Abstract
Idelalisib (ILB) is a selective phosphatidylinositol-3-kinase delta inhibitor approved for the treatment of hematological malignancies. However, ILB frequently causes hepatotoxicity, and the exact mechanism remains unclear. The current study profiled the metabolites of ILB in mouse liver, urine, and feces. The major metabolites found in the liver were oxidized metabolite GS-563117 (M1) and ILB-glutathione (GSH) adduct (M2). These metabolic pathways were confirmed by analysis of urine and feces from mice treated with ILB. Identification of ILB-GSH adduct (M2) suggests the formation of reactive metabolites of ILB. We also found that M1 can produce reactive metabolites and form M1-GSH adducts. The GSH-conjugates identified in mouse liver were also found in the incubations of ILB and M1 with human liver microsomes. Furthermore, we illustrated that CYP3A4 and 2C9 are the key enzymes contributing to the bioactivation pathway of ILB and M1. In summary, our work revealed that both ILB and its major metabolite M1 can undergo bioactivation to produce reactive metabolites in the liver. Further studies are required to determine whether these metabolic pathways contribute to ILB hepatotoxicity.

PMID: 29896955 [PubMed - indexed for MEDLINE]

Combination of PARP inhibitor and temozolomide to suppress chordoma progression.

J Mol Med (Berl). 2019 Jun 14;:

Authors: Cao X, Lu Y, Liu Y, Zhou Y, Song H, Zhang W, Davis D, Cui J, Hao S, Jung J, Wu Q, Park DM, Yang C

Abstract
Chordoma, a malignant bone cancer, is highly resistant to conventional therapeutic approaches; this greatly limits radio- and chemotherapeutic options and disease management. In the present study, we investigated three patient-derived chordoma cell lines to elucidate the molecular mechanism of resistance to therapeutics. An in vitro high-throughput chemical screening assay and an in vivo xenograft model were used to identify novel chemosensitizers for chordoma. We found that patient-derived chordoma cell lines recapitulated disease phenotypes, which were highlighted by robust resistance to medical therapy manifested as lack of DNA damage accumulation. Mechanistically, the PARP DNA repair pathway was found to play a central role in this resistance. Chemical screening confirmed that PARP inhibitors could strikingly enhance temozolomide (TMZ) therapy in chordoma cells. Combining the FDA-approved PARP inhibitor, olaparib, with chemotherapeutics not only potentiated DNA damage accumulation, cell cycle arrest, and apoptosis in vitro but also suppressed chordoma xenograft expansion in vivo. We conclude that combining PARP inhibition with TMZ could be an effective therapeutic approach for the clinical management of chordoma. KEY MESSAGES: The PARP DNA repair pathway enhances chemoresistance in chordoma cells. Combining PARP inhibitors with genotoxic agents induces chordoma cell cytotoxicity. PARP inhibitor combining with temozolomide suppresses growth of chordoma in vivo.

PMID: 31201471 [PubMed - as supplied by publisher]