Multiple Drug Combinations Research Articles

3D printed microfluidic chip for multiple anticancer drug combinations

Multi-drug combinations therapy is a promising method in the fight against cancer cells. Multi-drug combinations cannot be practically elucidated using conventional devices owing to structural limitations or operational complexity. 3D printing has recently attracted attention as a way to fabricate complicated and interconnected microfluidic channels, which is of design flexibility. Here, an easy-to-use, high-throughput, multi-drug combinations 3D printed microfluidic chips were brought forward. 36 discrete concentration combinations have been generated by repeated splitting-and-mixing of four inlet drugs in interconnected network channels, which are used to determine the optimal concentration of inhibition of cancer cells survival. We evaluate the potential to advance multi-drug combinations efficiency by optimizing the geometric parameters of tree-shaped branch unit, as well as the chip performance by dye visualization. The microfluidic chip was further applied to study multi-drug combinations responses, and the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay was employed to test the cytotoxic effect of four drugs combinations on A549. The experiment results demonstrated clinically relevant antagonistic, synergistic interactions between the four different antitumor drugs. Moreover, this chip has outstanding features, e.g., more compact structure, more accurate combination of concentrations, greater space for scalability. As such, it will be an effective multi-drug combinations screening platform for applications in biomedical research and clinical medicine.

Electrical Control in Neurons by the Ketogenic Diet.

The ketogenic diet is used as a diet treatment for drug-resistant epilepsy, but there are no antiepileptic drugs based on the ketogenic diet. The ketogenic diet changes energy metabolites (ketone bodies, glucose and lactate) in the brain, which consequently changes electrical activities in neurons and ultimately suppresses seizures in epileptic patients. In order to elucidate the antiseizure effects of the ketogenic diet, it is important to clarify the mechanism by which these metabolic changes are converted to electrical changes in neurons. In this review, we summarize electrophysiological studies focusing on electrical control in neurons by the ketogenic diet. Recent studies have identified electrical regulators driven by the ketogenic diet: ion channels (ATP-sensitive K+ channels and voltage-dependent Ca2+ channels), synaptic receptors (AMPA-type glutamate receptors and adenosine A1 receptors), neurotransmitter transporters (vesicular glutamate transporters), and others (BCL-2-associated agonist of cell death and lactate dehydrogenase). Thus, the ketogenic diet presumably elicits neuronal inhibition via the combined actions of these molecules. From the viewpoint of drug development, these molecules are valuable as targets for the development of new antiepileptic drugs. Drug therapy to mimic the ketogenic diet may be feasible in the future, through the combination of multiple antiepileptic drugs targeting these molecules.

Abstract CT142: Multidrug analyses in cancer patients via intratumoral microdosing with CIVO: A functional approach to precision oncology

Abstract The vision of a precision medicine-guided approach to novel cancer drug development is challenged by high intra-tumor heterogeneity, interpatient diversity, and complex interactions between tumor cells and the surrounding microenvironment. Attempts to model this complexity through the use of ex vivo systems have failed to accurately represent tumor biology, and resulting predictions of clinical drug efficacy have met with limited success. The era of genomics, highlighted by remarkable advances in high-throughput next generation sequencing technology, has sparked hope that this issue can be solved through a precision medicine approach to cancer treatment: matching the right drugs to the right patients. However, despite a few noteworthy successes pairing targeted agents with oncogenic driver mutations, genome-based precision medicine has been limited by an incomplete understanding of the relationship between cancer mutations and drug responsiveness. To overcome these issues, we developed CIVO (Comparative In Vivo Oncology), an arrayed microinjection technology that evaluates tumor responsiveness to microdoses of multiple drugs simultaneously and directly in a patient's tumor. CIVO consists of a multidrug injection device, fluorescent tracking microspheres which accurately denote the position of each drug injection site, and automated image analysis tools capable of quantifying both tumor cell and microenvironmental biomarkers of response to local drug exposure. Here we present preliminary data on the first 4 patients from our clinical feasibility study in soft tissue sarcoma. No unexpected adverse events related to microdose injection were observed. Consistent with historical clinical data, front line agent doxorubicin induced localized increases in markers for DNA damage, tumor cell apoptosis, and macrophage infiltration, whereas gemcitabine did not induce any observable local responses. Doxorubicin also induced tumor cell responses that suggest potential mechanisms of resistance to single agent therapy, including upregulation of PDGFαR and ERK phosphorylation. Multidrug investigation via intratumoral microinjection with CIVO in patients with soft tissue sarcoma appears safe and feasible. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors across a diverse immune competent patient population provides an innovative and exciting functional approach to complement current precision oncology strategies and enables deep characterization of cancer biology in early drug development. Citation Format: Matthew J. Thompson, Darin J. Davidson, Jessica A. Bertout, Kimberly H. Sottero, Marc O. Grenley, Emily Beirne, Richard A. Klinghoffer, Seth M. Pollack. Multidrug analyses in cancer patients via intratumoral microdosing with CIVO: A functional approach to precision oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT142.

Abstract 4032: Pharmacogenomic analysis of acquired resistance can reveal effective drug combination in glioblastoma

Abstract Targeted cancer therapies have produced substantial clinical responses, but glioblastoma multiforme (GBM) has poor response due to developing resistance. The goal is thus to design strategies to overcome resistance to targeted drugs. To address this, we have embarked on a new type of screening for resistant targets, by developing acquired resistant glioma models and using pharmacogenomic platform to identify the resistant targets. We have established several patient-derived in vivo glioma stem cells (GSC) models using a PI3K specific inhibitor BKM-120 by a selective pressure after a chronic drug treatment. The resistant cells were subjected to RNA-seq analysis as well as pharmacologic analysis utilizing high-throughput kinase drug library screening. Analysis of integrated RNA-seq and kinase drug library screening of resistant cells identified multiple effective drug combination. Activation of Aurora kinase A (Aurora A)/Polo-like kinase 1 (Plk1)/cyclin-dependent kinase (CDK) signaling pathway was predominant in resistant GSCs. Concomitant targeting of PI3K together with Aurora A, Plk1 or CDK1 had a synergistic growth inhibitory effect. In addition, the combined inhibition of Plk1 and PI3K resulted in tumor growth suppression and significant delay of acquired resistance in vivo. These observations suggest that cell cycle pathway serves as a major survival signal upon PI3K inhibition and provides a rationale for the combined use of PI3K and cell cycle inhibition to prevent acquired resistance in human GBM. Citation Format: Xiaolong Li, Juan Martinez-Ledesma, Chen Zhang, Feng Gao, W.K. Alfred Yung, Dimpy Koul. Pharmacogenomic analysis of acquired resistance can reveal effective drug combination in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4032.

Research progress of neoadjuvant therapy for locally advanced rectal cancer

The clinical application of novel chemotherapeutic drugs including oral 5-FU and targeted drugs and preoperatively accurate imaging grading has brought challenges to the indication criteria developed by NCCN and ESMO for neoadjuvant chemoradiotherapy in locally advanced rectal cancer (LARC). Extended hotspots have focused on the effectiveness of using capecitabine instead of fluorouracil infusion, the combination of multiple drugs and the feasibility of using neoadjuvant chemotherapy instead of neoadjuvant chemoradiotherapy for selective patients. Traditionally, the evaluation of the effect of neoadjuvant therapy has been based on the effect on the pathological complete remission (pCR) rate. However, current studies recommend the disease-free survival (DFS) as a more important outcome. Besides, seeking for effective biomarkers as predictive markers for neoadjuvant therapies or as prognostic markers remains a hotspot in the field of neoadjuvant chemoradiotherapy. The "watch and wait" approach refers to taking a close follow-up strategy instead of direct operation for patients achieving clinically complete remission (cCR) after neoadjuvant therapy. However, there is no unified evaluation criteria and time point for the evaluation of cCR following neoadjuvant therapy. Therefore, there remain a lot of controversies regarding the clinical application of neoadjuvant chemoradiotherapy in LARC. In this manuscript, research progress in the indication for neoadjuvant therapy, improvement in the neoadjuvant therapeutic schedule, advancement of the efficacy evaluation criteria of neoadjuvant therapy, the "watch and wait" approach and other hot topics is summarized to provide references for clinical practice.

THE PREVALENCE OF RESISTANT AND UNDERCONTROLLED HYPERTENSION AMONG PATIENTS OF A HYPERTENSION OUTPATIENT CLINIC IN SZEGED

Objective: In Hungary, between 2005–2009 around 57% of hypertensive patients did not reach the goal blood pressure (BP). Design and method: In one of the Hypertension Outpatient Clinics of the 1st Department of Medicine Nephrology-Hypertension Center in Szeged 310 patients’ data were analyzed. Means of two measurements were calculated. The goal SBP was 140/ mm Hg. Means ± SD are reported. Results: The mean age of hypertensive patients was 61.4 ± 14.3 years. The mean duration of HT was 14.2 ± 12.0 years. Among these 310 HT patients 115 (37%) were men (age 58.2 ± 15.6 years) and 195 (63%) women (age 63.4 ± 13.1 years). BP of 186/310 (60%) patients were in goal range (SBP 124 ± 9 mm Hg) and 124/310 (40%) were not (SBP 155 ± 17 mm Hg). Among the 310 patients 45 (15%) had only DM as additional risk factor, type-1 and type-2 together. Twenty-one (17%) of 124 HT patients with undercontrolled BP had diabetes mellitus (DM) (BP 149 ± 15/89 ± 8 mm Hg). By the definition of RHT alltogether 234/310 (76%) patients had RHT (BP 158 ± 17/97 ± 8 mm Hg) in this population. But 257/310 (83%) patients were taking 3 or more antihypertensive drugs, and their SBP was 136 ± 20 mm Hg. The difference (n = 23) between 257 and 234 were the patients with 3 drugs but reaching the goal SBP. With combinations of 4 or more drugs 111 of the 234 (47%) RHT patients had BP < 140/90 mm Hg and 63 (27%) of patients with 4 or more drugs them didn’t reach the goal BP. Among the multiple drug combinations, 83/310 (27%) patients were taking 3 antihypertensive drugs, 65/310 (21%) 4 drugs, 48/310 (15%) 5 drugs, 34/310 (11%) 6 drugs, 20/310 (6%) 7 drugs and 7/310 (2%) 8 drugs. Fifteen patients were on monotherapy, their BP were 124 ± 12/79 ± 9 mm Hg, and only 1 of them was undercontrolled (BP 154/100 mm Hg). All the patients taking 2 drugs were in goal range. Conclusions: A fourfold combination of antihypertensive agents was the most frequent in this population. The most frequent drug classes were the ACEIs and/or ARBs, the DHP-CCBs and the thiazide diuretics.

Non-tuberculous Mycobacterial Infections in Thoracic Transplant Candidates and Recipients.

To review and discuss the epidemiology, risk factors, clinical presentation, diagnosis, and treatment of non-tuberculous mycobacteria (NTM) in thoracic transplantation. Non-tuberculous mycobacteria are ubiquitous but are an uncommon cause of disease after solid organ transplantation. The incidence of infection is higher in thoracic transplant recipients than in abdominal transplant recipients, with most cases seen after lung transplantation. It is associated with increased morbidity and, occasionally, mortality. Infection in the pre-transplant setting can occur in lung transplant candidates, often posing a dilemma regarding transplant listing. Disease manifestations are diverse, and pulmonary disease is the most common. Diagnosis requires a high index of suspicion. Treatment requires a multiple-drug combination and is limited by drug-drug interactions and tolerability. Mycobacterium abscessus is a challenge in lung transplant recipients, due to its intrinsic resistance and propensity to relapse even after prolonged therapy. Mycobacterium chimaera is an emerging pathogen associated with contamination of heater-cooler units and is described to cause disease months after cardiothoracic surgery. NTM infections in thoracic organ transplant recipients are uncommon but are associated with substantial morbidity and mortality. Data from larger multicenter studies is needed to better define the epidemiology of NTM in thoracic transplantation, best treatment options, and the management of infected transplant candidates.

Treatment regimens by pediatric nephrologists in children with congenital nephrogenic diabetes insipidus: A MWPNC study .

Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder affecting urinary concentration. Clinicians have varied medication regimens as well as nutritional plan approaches for these children. An electronic survey was distributed to member pediatric nephrologists of the Midwest Pediatric Nephrology Consortium via email (n=179). Questions included types of drugs prescribed, factors contributing to drug choice, common drug combinations given, and dietary/failure to thrive interventions used. We analyzed results from 72 respondents (42% overall response rate). 72% treated only 1 - 3 patients with NDI per year, 12% treated 4 or more, and 17% had no NDI patients. Of providers treating NDI patients, almost all prescribed thiazides (93%), 62% prescribed amiloride, and 55% reported prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) as part of their drug regimen. gastrointestinal (GI) and renal side effects (43%) were given as reasons for not prescribing indomethacin. For 70%, drug choice was determined by severity of failure to thrive (FTT). Physicians were asked to define the most common drug combinations they prescribed. 48% reported prescribing indomethacin with hydrochlorothiazide. 84% of respondents have a renal dietitian on staff, and half included appointments with a dietitian as part of FTT therapy. The most common intervention for FFT was gastrostomy tube placement (78%). Our results suggest consensus on the use of thiazides, while the use of indomethacin is limited by GI and renal side effect profile. Our results revealed that multiple drug combinations are frequently used without one specific preferred regimen. .

Establishment and verification of risk assessment scale for clinical safety medication of aconitine

Chinese patent medicine containing aconitine is the key in clinical rational drug use. These drugs contain Chuanwu, Caowu or Fuzi, and Aconitum brachypodum with functions of expelling wind-dampness or tonifying Yang, all of which shall be used by strictly following the indications and dosage. However, there are many kinds of such drugs. Not only the unfamiliar knowledge of some Chinese and Western physicians about the characteristics of them, but also the combination of multiple drugs from different clinical departments, would increase the risk of aconitine poisoning. Based on the previous research, this paper proposed three core elements "syndrome differentiation-dosage differentiation-toxicity differentiation" from the prescription review and pharmacy consulting work, and objective and standardized evaluation was used to build a risk assessment scale containing 3 categories, 9 items and 36 indicators with Hulisan Jiaonang and Qufeng Zhitong Jiaonang as the example. This scale was used to evaluate the risk of a therapeutic regimen before and after the implementation. According to the verification of the existing adverse reaction cases, the risk assessment scale can be used to indicate the risk of drug treatment program and identify the risk level of drug treatment status. This paper tried to provide a methodological paradigm for scientific and objective evaluation on the safety of Chinese patent medicines, and help to identify the key links and risk prevention in the rational use by Chinese medicine physicians and pharmacists.

Role of Drug Metabolic Enzymes and Transporters in Drug-Drug Interactions Between Antiretroviral and Antituberculosis Drugs

Drug-drug interactions is one of the major determinant in drug development and clinical applications. Individual differences in pharmacokinetics may cause extensive variability in drug efficacy, toxicity and adverse drug reactions, and represent a major concern in drug development. According to world health organization, an estimated 1.2 million patients were diagnosed with HIV/TB coinfection in 2015, and approximately 400,000 coinfected individuals were died in 2016. During treatment of tuberculosis and human immunodeficiency virus (HIV) coinfections, a combination of multiple therapeutic drugs is used, which is potential for interactions between coadministered drugs. Drug metabolizing enzymes and transporters plays vital role in the disposition, pharmacokinetics as well as efficacy and toxicity of many antituberculosis (anti-TB) and antiretroviral (ARVs) drugs. The current understanding of drug-drug interactions involving the first-line antituberculosis and antiretroviral (ARVs) drugs are reviewed and summarized in this article emphasizing the role of drug transporters and metabolic enzymes. It is found that several clinical drug-interactions are caused by the phase I and II metabolic enzymes (cytochrome-P-450s, CYPs, UDP-glucuronosyltransferases, UGTs) and uptake/ efflux transporters, particularly permeability glycoprotein, brest cancer resistance protein, multidrug resistance protein and solute carrier transporters). Overall, this study will be helpful to understand the drug-interactions between the ARV or anti-TB drug regimen or with concomitantly used drugs at a glance. By understanding the unique functions and characteristics of enzymes and transporters, it may use in the management of drug interactions in the treatment of HIV and TB. Keywords: Drug-drug interactions, Metabolic Enzymes, Membrane Transporters, Antiretroviral and antituberculosis drugs

A study of the effectiveness of multiple drug combination therapies for vertebrobasilar insufficiency diagnosed from the medical history

A study of the effectiveness of multiple drug combination therapies for vertebrobasilar insufficiency diagnosed from the medical history

Rates of glycaemic deterioration in a real-world population with type 2 diabetes

Aims/hypothesisThere is considerable variability in how diabetes progresses after diagnosis. Progression modelling has largely focused on ‘time to failure’ methods, yet determining a ‘coefficient of failure’ has many advantages. We derived a rate of glycaemic deterioration in type 2 diabetes, using a large real-world cohort, and aimed to investigate the clinical, biochemical, pharmacological and immunological variables associated with fast and slow rates of glycaemic deterioration.MethodsAn observational cohort study was performed using the electronic medical records from participants in the Genetics of Diabetes Audit and Research in Tayside Study (GoDARTS). A model was derived based on an individual’s observed HbA1c measures from the first eligible HbA1c after the diagnosis of diabetes through to the study end (defined as insulin initiation, death, leaving the area or end of follow-up). Each HbA1c measure was time-dependently adjusted for the effects of non-insulin glucose-lowering drugs, changes in BMI and corticosteroid use. GAD antibody (GADA) positivity was defined as GAD titres above the 97.5th centile of the population distribution.ResultsThe mean (95% CI) glycaemic deterioration for type 2 diabetes and GADA-positive individuals was 1.4 (1.3, 1.4) and 2.8 (2.4, 3.3) mmol/mol HbA1c per year, respectively. A younger age of diagnosis, lower HDL-cholesterol concentration, higher BMI and earlier calendar year of diabetes diagnosis were independently associated with higher rates of glycaemic deterioration in individuals with type 2 diabetes. The rate of deterioration in those diagnosed at over 70 years of age was very low, with 66% having a rate of deterioration of less than 1.1 mmol/mol HbA1c per year, and only 1.5% progressing more rapidly than 4.4 mmol/mol HbA1c per year.Conclusions/interpretationWe have developed a novel approach for modelling the progression of diabetes in observational data across multiple drug combinations. This approach highlights how glycaemic deterioration in those diagnosed at over 70 years of age is minimal, supporting a stratified approach to diabetes management.

Comparison of long-term follow-up outcomes between multiple-drugs combination therapy and tonsillectomy pulse therapy for pediatric IgA nephropathy.

To clarify the long-term efficacy of multiple-drugs combination therapy (PWDM) and tonsillectomy pulse therapy (TPT) for pediatric IgA nephropathy (IgAN), we retrospectively evaluated the clinical and laboratory findings as well as the prognosis for IgAN patients treated with each treatment at long-term follow-up. We collected data on 61 children who had been diagnosed with severe IgAN. The children were retrospectively divided into two groups. Group 1 consisted of 44 severe IgAN children treated with PWDM, and Group 2 consisted of 17 severe IgAN children treated with TPT. The clinical features, pathological findings, and prognosis were analyzed for both groups. The mean urinary protein excretion, serum creatinine, IgA levels, MESTCG scores, and percentage of glomeruli showing crescents in both groups at the second renal biopsy were lower than those at the first renal biopsy. At the time of the second biopsy, the IgA level in Group 2 was lower than that in Group 1; however, there were no significant differences in the mean urinary protein excretion, frequency of hematuria, serum albumin, creatinine, or e-GFR between the two groups. At the most recent follow-up, there were no significant differences in prognosis between the groups. Our study suggested that PWDM and TPT are effective in ameliorating urinary abnormalities and improving the long-term outcome of pediatric IgAN.

Experimental design for multi-drug combination studies using signaling networks.

Combinations of multiple drugs are an important approach to maximize the chance for therapeutic success by inhibiting multiple pathways/targets. Analytic methods for studying drug combinations have received increasing attention because major advances in biomedical research have made available large number of potential agents for testing. The preclinical experiment on multi-drug combinations plays a key role in (especially cancer) drug development because of the complex nature of the disease, the need to reduce development time and costs. Despite recent progresses in statistical methods for assessing drug interaction, there is an acute lack of methods for designing experiments on multi-drug combinations. The number of combinations grows exponentially with the number of drugs and dose-levels and it quickly precludes laboratory testing. Utilizing experimental dose-response data of single drugs and a few combinations along with pathway/network information to obtain an estimate of the functional structure of the dose-response relationship in silico, we propose an optimal design that allows exploration of the dose-effect surface with the smallest possible sample size in this article. The simulation studies show our proposed methods perform well.

A superposable double-gradient droplet array chip for preparation of PEGDA microspheres containing concentration-gradient drugs

This article describes a superposable double-concentration-gradient droplet array chip, which allows a variety of concentration combinations of two components to be formed simultaneously. The concentration gradients generated from two layers of the chip could be arbitrarily superimposed by adjusting the center angle between the two bonding layers. With the aqueous phase flow rate of 1.0 μL min−1 and the oil phase flow rate of 30.0 μL min−1, the droplets about 58 μm in diameter were produced, and the coefficients of variation were below 6.0% for single channel and 5.7% for all the channels. Using a dual-32-channel superposable gradient droplet array chip, poly(ethylene glycol) diacrylate (PEGDA) microspheres containing concentration-gradient combinations of rhodamine B and fluorescein were fabricated to demonstrate the capability of PEGDA for encapsulating hydrophilic and hydrophobic substances, as well as the proper concentration-gradient distribution. Furthermore, PEGDA microspheres loaded with two anticancer drugs, hydrophilic doxorubicin hydrochloride and hydrophobic paclitaxel, of 17 concentration combinations were simultaneously prepared. The drug-induced apoptosis of human uterine cervix cancer cells was investigated using the dual-drug-loaded PEGDA microspheres. The optimum synergistic concentration combination of the two drugs was 12.5 μg mL−1 for doxorubicin hydrochloride and 43.75 μg mL−1 for paclitaxel according to the preliminary screening. The superposable double-gradient droplet array generator was demonstrated to be a promising platform for screening multiple drug combination in microcarriers.

Cardiac arrhythmias related to psychiatric medication

SummaryThis narrative review summarizes current available information about cardiac arrhythmias (QT prolongation, Torsade de pointes Tachycardia [TdP], sudden cardiac death) associated with psychiatric medication. Among the most commonly used antipsychotics, amisulpride and ziprasidone are most frequently associated with TdP. Treatment with some antidepressants (SSRIs, tricyclic antidepressants) is associated with a 5- to 6-fold increase in the incidence of out-of-hospital cardiac arrest. Lithium is associated with bradycardia, T-wave changes and AV-block; anxiolytics of the benzodiazepine group do usually not have cardiac side effects. The combination of multiple drugs (including medications from general medicine) that prolong the QT interval has a particularly high cardiac risk.

Comparison of three dimensional synergistic analyses of percentage versus logarithmic data in antiviral studies

Cell culture antiviral experiments were conducted in order to understand the relationship between percentage data generated by plaque reduction (PR) and logarithmic data derived by virus yield reduction (VYR) assays, using three-dimensional MacSynergy II software. The relationship between percentage and logarithmic data has not been investigated previously. Interpretation of drug-drug interactions is based on a Volume of Synergy (VS) calculation, which can be positive (synergy), negative (antagonistic), or neutral (no or minimal interaction). Interactions of two known inhibitors of vaccinia virus replication, cidofovir and 6-azauridine, used in combination by PR assay yielded a VS value of 265, indicative of strong synergy. By VYR, the VS value was only 37, or weak synergy using the same criterion, even though profound log10 reductions in virus titer occurred at multiple drug combinations. These results confirm that the differences in VS values is dependent of the measurement scale, and not that the degree of synergy differed between the assays. We propose that for logarithmic data, the calculated VS values will be lower for significant synergy and antagonism and that volumes of >10 μM2log10 PFU/ml (or other units such as μM2log10 genomic equivalents/ml or μM2log10 copies/ml) and <-10 μM2log10 PFU/ml are likely to be indicative of strong synergy and strong antagonism, respectively. Data presented here show that the interaction of cidofovir and 6-azauridine was strongly synergistic in vitro.

Abstract 3139: In vivo functional analyses of cancer gene variants for cancer driver identification and drug discovery

Abstract Precision oncology requires identifying and understanding of cancer genome changes in a patient tumor tissue and finding the best cancer therapy targeting the changes. Although many cancer gene targets have been validated so far, next-generation genomic profile analyses have uncovered much more cancer gene variants with unconfirmed functions. Developing methods to functionally evaluate mutations/variants and understand their roles in cancer development and drug responses, such as drug resistance or synthetic lethality, will be critical in cancer treatment decision support. In addition, in some clinical cases, multiple treatment choices such as multiple drug combinations exist. Developing cancer models which can test multiple treatments will provide direct comparison of those therapies and select the best options. At GenenDesign, we have performed drug tests on mouse “avatars”, which are also known as Patient-Derived Xenograft (PDX) models. They are personalized cancer models derived from patient tumor samples with cancer mutation profiles and drug responses very similar to the corresponding cancer patients. Drug screenings were carried out in avatars by testing chemotherapies or targeted drugs against specific cancer gene mutations and variants. Selected drugs or drug combinations from avatar studies have been applied to corresponding patients with highly consistent treatment outcome. From genomic profile analysis of our near 1500 PDX tumor models in cancer types such as lung, colorectal, gastric, liver, and esophageal, we are able to identify a large number of cancer gene mutations/variants, gene fusions, as well as gene copy number and RNA expression changes in major cancer signal pathways such as EGFR, Her2, c-Met/ALK, Ras/Raf, FGFRs, PI3K/Akt, Wnt, Notch, DNA repair, cell cycle regulation, angiogenesis. Many of these gene aberrations are potential drug targets and have been functionally tested in PDX models with approved drugs or clinical drug candidates. The mutation/variant information and drug response information generated from PDX models have been organized into our Precision Cancer Information Lab database. Patient tumor DNA test results have been used for searching genetically matched PDX models in our database. Once matched PDX models are identified, the available drug response information can be used as evidence for clinical treatment decision. In addition, the matched PDX models can also been used to test more treatment options such as different combinations and new clinical drug candidates. Citation Format: Jingjing Jiang, Tengfei Yu, Ying Yan, Wei Du, Tingting Tan, Xuqin Yang, Jiali Gu, Ling Qiu, Xin K. Ye, Zhenyu Gu. In vivo functional analyses of cancer gene variants for cancer driver identification and drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3139. doi:10.1158/1538-7445.AM2017-3139

Abstract 755: Supporting precision cancer treatment decision with functional evaluation of cancer gene mutations and variants

Abstract Precision oncology requires identifying and understanding of cancer genome changes in a patient tumor tissue and finding the best cancer therapy targeting the changes. Although many cancer gene targets have been validated so far, next-generation genomic profile analyses have uncovered much more cancer gene variants with unconfirmed functions. Developing methods to functionally evaluate mutations/variants and understand their roles in cancer development and drug responses, such as drug resistance or synthetic lethality, will be critical in cancer treatment decision support. In addition, in some clinical cases, multiple treatment choices such as multiple drug combinations exist. Developing cancer models which can test multiple treatments will provide direct comparison of those therapies and select the best options. At GenenDesign, we have performed drug tests on mouse “avatars”, which are also known as Patient-Derived Xenograft (PDX) models. They are personalized cancer models derived from patient tumor samples with cancer mutation profiles and drug responses very similar to the corresponding cancer patients. Drug screenings were carried out in avatars by testing chemotherapies or targeted drugs against specific cancer gene mutations and variants. Selected drugs or drug combinations from avatar studies have been applied to corresponding patients with highly consistent treatment outcome. From genomic profile analysis of our near 1500 PDX tumor models in cancer types such as lung, colorectal, gastric, liver, and esophageal, we are able to identify a large number of cancer gene mutations/variants, gene fusions, as well as gene copy number and RNA expression changes in major cancer signal pathways such as EGFR, Her2, c-Met/ALK, Ras/Raf, FGFRs, PI3K/Akt, Wnt, Notch, DNA repair, cell cycle regulation, angiogenesis. Many of these gene aberrations are potential drug targets and have been functionally tested in PDX models with approved drugs or clinical drug candidates. The mutation/variant information and drug response information generated from PDX models have been organized into our Precision Cancer Information Lab database. Patient tumor DNA test results have been used for searching genetically matched PDX models in our database. Once matched PDX models are identified, the available drug response information can be used as evidence for clinical treatment decision. In addition, the matched PDX models can also been used to test more treatment options such as different combinations and new clinical drug candidates. Citation Format: Jingjing Jiang, Zhongguang Luo, Jia Wei, Guanglei Zhuang, Song Yi, Ying Yan, Tengfei Yu, Wei Du, Tingting Tan, Ling Qiu, Jiali Gu, Xin K. Ye, Jie Liu, Zhenyu Gu. Supporting precision cancer treatment decision with functional evaluation of cancer gene mutations and variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 755. doi:10.1158/1538-7445.AM2017-755

The prevalence of resistant and undercontrolled hypertension among patients of a Hypertension Outpatient Clinic

Introduction. Around 57% of Hungarian hypertensive patients did not reach the goal blood pressure. According to an ESH Newsletter published in 2011, the prevalence of resistant hypertension is 2.9–43%. Objective. Analysing only the therapy of hypertensive patients of the Hypertension Outpatient Clinic of the University of Szeged, the authors wanted to answer following main questions: How many patients were therapeutically resistant according to the definition of resistant hypertension? How many patients were taking 3 or more antihypertensive drugs? How many of these patients reached target SBP values? How many drugs were usually used in combination therapy? Material and methods. Data were retrospectively collected from 01/01/2011 to 31/08/2011 from the electronic files of the hypertensive patients. Altogether 310 patients’ data were analysed, of all cases only one visit was taken into account. For those patients who visited the Clinic more than once during this period, only the first visit was considered. Means of two measurements were calculated. The goal SBP was 140 mmHg. Results. In this population, 234/310 (76%) patients had resistant hypertension according to the definition (158 ± 17/97 ± 8 mmHg). Three or more antihypertensive drugs were taken by 257/310 (83%) patients (136 ± 20 mmHg) and 134 of them (52% of 257 patients) reached the therapeutic goal. A fourfold combination of antihypertensive agents was the most frequent in this population. Conclusion. It is advised to use multiple drug combinations and it is recommended to spend enough time but not longer than necessary to find the most effective combination in every case.