A Genetic Score Associates With Pioglitazone Response in Patients With Non-alcoholic Steatohepatitis.

Front Pharmacol. 2018;9:752

Authors: Kawaguchi-Suzuki M, Cusi K, Bril F, Gong Y, Langaee T, Frye RF

Abstract
Pioglitazone is used effectively to treat non-alcoholic steatohepatitis (NASH), but there is marked variability in response. This study examined whether genetic variation contributes to pioglitazone response variability in patients with NASH. This genetic substudy includes 55 participants of a randomized controlled trial designed to determine the efficacy of long-term pioglitazone treatment in patients with NASH. The primary outcome of the clinical trial was defined as ≥2-point reduction in the non-alcoholic fatty liver disease activity score (NAS). In this substudy, single nucleotide polymorphisms (SNPs) in putative candidate genes were tested for association with primary and secondary outcomes. A genetic response score was constructed based on the sum of response alleles for selected genes. The genetic response score was significantly associated with achievement of the primary outcome (odds ratio 1.74; 95% CI 1.27-2.54; p = 0.0015). ADORA1 rs903361 associated with resolution of NASH (p = 0.0005) and change in the ballooning score among Caucasian and Hispanic patients (p = 0.0005). LPL rs10099160 was significantly associated with change in ALT (p = 0.0005). The CYP2C8∗3 allele, which confers faster pioglitazone clearance in allele carriers, was associated with change in fibrosis score (p = 0.026). This study identified key genetic factors that explain some of the inter-individual variability in response to pioglitazone among patients with NASH.

PMID: 30065651 [PubMed]

Identification of Novel Protein Expression Changes Following Cisplatin Treatment and Application to Combination Therapy.

J Proteome Res. 2017 Nov 03;16(11):4227-4236

Authors: Stark AL, Madian AG, Williams SW, Chen V, Wing C, Hause RJ, To LA, Gill AL, Myers JL, Gorsic LK, Ciaccio MF, White KP, Jones RB, Dolan ME

Abstract
Determining the effect of chemotherapeutic treatment on changes in protein expression can provide important targets for overcoming resistance. Due to challenges in simultaneously measuring large numbers of proteins, a paucity of data exists on global changes. To overcome these challenges, we utilized microwestern arrays that allowed us to measure the abundance and modification state of hundreds of cell signaling and transcription factor proteins in cells following drug exposure. HapMap lymphoblastoid cell lines (LCLs) were exposed to cisplatin, a chemotherapeutic agent commonly used to treat testicular, head and neck, non-small cell lung, and gynecological cancers. We evaluated the expression of 259 proteins following 2, 6, and 12 h of cisplatin treatment in two LCLs with discordant sensitivity to cisplatin. Of these 259 proteins, 66 displayed significantly different protein expression changes (p < 0.05). Fifteen of these proteins were evaluated in a second pair of LCLs with discordant sensitivities to cisplatin; six demonstrated significant differences in expression. We then evaluated a subset of 63 proteins in a second set of LCLs with discordant sensitivity, and 40% of those that were significant in the first pair were also significant in the second part with concordant directionality (p < 0.05). We functionally validated one of the top proteins identified, PDK1, and demonstrated a synergistic relationship between cisplatin and a PDK1 inhibitor in multiple lung cancer lines. This study highlights the potential for identifying novel targets through an understanding of cellular changes in protein expression and modification following drug treatments.

PMID: 28902521 [PubMed - indexed for MEDLINE]

Feed My Heart or Eat It: miR-22 Decides.

J Am Coll Cardiol. 2016 10 04;68(14):1572-4

Authors: Matkovich SJ, Dorn GW

PMID: 27687199 [PubMed - indexed for MEDLINE]

Reply to: "miR-122 expression is not regulated during activation of hepatic stellate cells".

J Hepatol. 2016 10;65(4):868

Authors: Li J, Li S

PMID: 27388922 [PubMed - indexed for MEDLINE]

Medical Genetics Summaries

Book. 2012

Authors: Pratt V, McLeod H, Rubinstein W, Dean L, Malheiro A

Abstract
Carvedilol (brand name Coreg) is used to treat heart failure and high blood pressure (hypertension). It is also used in patients who developed left ventricular dysfunction after having a heart attack (myocardial infarction, MI). In patients with cardiovascular disease, carvedilol is associated with improvements in quality of life, hospitalization rates, and survival. Carvedilol is a non-selective beta blocker (beta 1 and beta 2) and an alpha 1 blocker. It reduces the energy demands on the heart by blocking cardiac beta receptors, which decreases the heart rate and the force of heart contractions. Carvedilol lowers blood pressure by blocking alpha receptors on blood vessels, which relaxes and dilates blood vessels. CYP2D6 is one of the primary enzymes involved in activating and metabolizing carvedilol. Approximately 8% of Caucasians and 2% of most other populations have absent CYP2D6 activity and are predicted to be “CYP2D6 poor metabolizers.” The FDA-approved drug label for carvedilol states that plasma concentrations of carvedilol may be higher in CYP2D6 poor metabolizers compared to normal metabolizers, but does not discuss altering carvedilol dosing based on a patient’s CYP2D6 genotype (1). However, the label does state the dose of carvedilol should be individualized, and the dose should be monitored as it is gradually increased (up-titrated), based on tolerability and clinical response (Table 1). The Dutch Pharmacogenetics Working Group (DPWG) of the Royal Dutch Association for the Advancement of Pharmacy (KNMP) recommend that no action is needed for carvedilol and CYP2D6 genotype. For CYP2D6 poor metabolizers, DPWG states that the plasma concentration of carvedilol can be elevated, but this does not result in an increase in side effects (Table 2) (2).

PMID: 30067327

Current Statistical Metrics Are Pragmatic Measures to Compare the Predictive Quality of Preclinical Assays.

Toxicol Sci. 2018 Jun 22;:

Authors: Ingelman-Sundberg M, Lauschke VM

PMID: 30063796 [PubMed - as supplied by publisher]

Alpha adducin (ADD1) gene polymorphism and new onset of diabetes under the influence of selective antihypertensive therapy in essential hypertension.

Curr Hypertens Rev. 2018 Jul 30;:

Authors: Gupta S, Jhawat V, Agarwal BK, Roy P, Saini V

Abstract
BACKGROUND: Different antihypertensive therapies (especially diuretics) are reported to induce new onset of diabetes in some hypertensive patients. α-adducin-1 (ADD1) gene is salt sensitive gene which has its role in etiology of hypertension via salt sensitivity. Therefore, the G460T polymorphism of ADD1 gene may be associated with new onset of diabetes under the influence of diuretic and other antihypertensive therapies.
AIM: To assess the correlation between genetic polymorphism (ADD1 G460T polymorphism) and glycaemic disturbance under influence of diuretic and other antihypertensive drug therapies.
MATERIALS AND METHODS: We recruited study subjects, 270 normotensive as control (150 male and 120 females), 270 hypertensive patients (95 male and 175 females) and 240 hypertensive with new onset of diabetes patients (80 male and 160 females). All study samples were genotyped for ADD1 polymorphic alleles and analyzed the relationship between different genotypes with respect to anthropometric and clinical parameters along with drug therapies.
RESULTS: Clinical and anthropometric parameters (such as age, SBP, DBP, FBG, height, weight, WC, HP, W/H ratio, and BMI) of study population were found highly statistically significant (p<0.05) at base value. Further, genotype wise comparison of all above parameters revealed most of them as non-significant (p>0.05). Whereas, comparison between genotype and different antihypertensive drug therapy of hypertensive patients, specifically, diuretic therapy as mono in male (p=0.0227) and female (p=0.0292) and in combination with BBs in both male (p=0.0023) and female (p=0.0079) revealed a higher FBG level in variant T allele. In case of hypertensive with new onset of diabetes patients, only female population showed a slightly statistical significant (p=0.0413) difference in FBG level with diuretic mono therapy. Other antihypertensive drug therapies were safe and effective either as mono or in combination therapy.
DISCUSSION: Anthropometric parameters may be the indicative factors for hypertension and diabetes. Variant T allele of ADD1 gene may be considered as the risk factor for development of diabetes in hypertensive patients. Diuretics as mono therapy and in combination with BBs may be considered as the risk factor for new onset of diabetes in EH patients carrying variant T allele (either as TG or TT).

PMID: 30062972 [PubMed - as supplied by publisher]

Hepatic mitochondrial adaptations to physical activity: impact of sexual dimorphism, PGC1α, and BNIP3 mediated mitophagy.

J Physiol. 2018 Jul 31;:

Authors: Von Schulze A, McCoin CS, Onyekere C, Allen J, Geiger P, Dorn GW, Morris EM, Thyfault JP

Abstract
KEY POINTS SUMMARY: Hepatic mitochondrial adaptations to physical activity may be regulated by mitochondrial biogenesis (PGC1α) and mitophagy (BNIP3). Additionally, these adaptations may be sex-dependent. Chronic increases in physical activity lowers basal mitochondrial respiratory capacity in mice. Female mice have higher hepatic ETS protein content, elevated respiratory capacity, lowered mitophagic flux, and emit less mitochondrial H2 O2 independent of physical activity. Males require chronic daily physical activity to attain a similar mitochondrial phenotype compared to females. In contrast, females have limited hepatic adaptations to chronic physical activity. Livers deficient in PGC1α and BNIP3 display similar mitochondrial adaptations to physical activity as those found in wild type mice.
ABSTRACT: Hepatic mitochondrial adaptations to physical activity may be regulated by biogenesis- and mitophagy-associated pathways in a sex-dependent manner. Here, we tested if mice with targeted deficiencies in liver-specific PGC1α (LPGC1α+/- ) and BNIP3-mediated mitophagy (BNIP3-/- ) would have reduced physical activity induced adaptations in respiratory capacity, H2 O2 emission, and mitophagy compared to wild type (WT) controls and if these effects were impacted by sex. Male and female WT, LPGC1α+/- , and BNIP3-/- C57BL6/J mice were divided into groups that remained sedentary (SED) or had access to daily physical activity via voluntary running wheels (VWR) (n = 6-10/group) for 4 weeks. Mice had ad libitum access to low-fat diet and water. VWR reduced basal mitochondrial respiration, increased mitochondrial coupling and altered ubiquitin-mediated mitophagy in a sex-specific manner in WT mice. Female mice in all genotypes displayed higher electron transport system content, increased ADP-stimulated respiration, produced less mitochondrial derived ROS, exhibited reduced mitophagic flux, and were less responsive to VWR compared to males. Males responded more robustly to VWR-induced changes in hepatic mitochondrial function resulting in a match to adaptations found in females. Deficiencies in PGC1α and BNIP3 alone did not largely alter mitochondrial adaptations to VWR. However, VWR restored sex-dependent abnormalities in mitophagic flux in LPGC1α+/- . Finally, BNIP3-/- mice had elevated mitochondrial content and increased mitochondrial respiration putatively through repressed mitophagic flux. In conclusion, mitochondrial adaptations to physical activity are more dependent on sex than PGC1α and BNIP3. This article is protected by copyright. All rights reserved.

PMID: 30062822 [PubMed - as supplied by publisher]

Entrepreneurialism in the Translational Biologic Sciences: Why, How, and However.

JACC Basic Transl Sci. 2018 Feb;3(1):1-8

Authors: Bristow MR, Leinwand LA, Olson EN

Abstract
Because they are perceived as distinct from the biological sciences, entrepreneurial pursuits may be daunting to the average researcher. In this report, we explain why academic scientists and in particular translational researchers should be naturally as well as rationally attracted to entrepreneurial endeavors. We go into some detail of how entrepreneurial achievements are actually accomplished and offer a few caveats for consideration when embarking down entrepreneurial pathways. We conclude that, although not for everyone, for translational investigators in the biologic sciences, entrepreneurial pursuits are desirable, accomplishable, and professionally rewarding.

PMID: 30062188 [PubMed]

Two common mutations within CYP2C19 affected platelet aggregation in Chinese patients undergoing PCI: a one-year follow-up study.

Pharmacogenomics J. 2018 Jul 31;:

Authors: Wang Z, Liu Z, Wang W, Fu Y, Chen W, Li W, Zhang X, Tang Y, Zhou Z

Abstract
The effect of dual antiplatelet therapy, clopidogrel combined with aspirin, was influenced by CYP2C19 gene mutation and heterogeneity of population. Related studies remained controversial and limited, especially in Chinese. Total 3295 unrelated ACS Chinese patients undergoing percutaneous coronary intervention (PCI) were recruited and followed up to 1 year. Meanwhile, baseline and clinical data were retrieved. CYP2C19*2 and *3 were genotyped by sequencing. Associations of variants and metabolic types with platelet reactivity (PR) were analyzed by a logistic regression model. And, a Cox proportional hazards model was utilized to analyze survival data. Confounders included gender, age, smoking status, dosage of aspirin and clopidogrel, and BMI. It was found that patients with allele A in CYP2C19*2 and *3 were susceptibility to high PR (OR, 95%CI and P values were 1.34, 1.20-1.50, <0.0001 and 1.42, 1.13-1.79, 0.0029, respectively) after taking clopidogrel. The PR increased along with the number of loss of function (LOF) allele increased and did in order of haplotype*1, *2, and *3. This research suggested that LOF alleles and risk haplotypes in CYP2C19 could significantly attenuate the response to clopidogrel, which resulted in platelet aggregation.

PMID: 30061570 [PubMed - as supplied by publisher]

Pharmacogenetics of ugt genes in North African populations.

Pharmacogenomics J. 2018 Jul 31;:

Authors: Gaibar M, Novillo A, Romero-Lorca A, Esteban ME, Fernández-Santander A

PMID: 30061569 [PubMed - as supplied by publisher]

Early target attainment of azithromycin therapy in children with lower respiratory tract infections.

J Antimicrob Chemother. 2018 Jul 27;:

Authors: Liu S, Zheng Y, Wu X, Xu B, Liu X, Feng G, Sun L, Shen C, Li J, Tang B, Jacqz-Aigrain E, Zhao W, Shen A

Abstract
Objectives: Early target attainment is the key factor influencing the outcome of antimicrobial therapy. The objective of the present study was to evaluate the relationship between azithromycin concentrations during the first 24-48 h of therapy and the clinical outcome in order to optimize antimicrobial therapy.
Methods: All children with lower respiratory tract infections receiving intravenous azithromycin monotherapy were included. The relationship between azithromycin trough concentrations during the first 24-48 h and the effectiveness and safety was explored.
Results: Data from 44 children [mean (SD) age = 5.25 (3.72) years] were available for final analysis. Children with trough concentrations >0.25 mg/L (n = 8) had a more significant improvement in antibacterial efficacy in terms of decreased C-reactive protein (P = 0.006) and the percentage of neutrophils (P = 0.043) compared with children with trough concentrations ≤0.25 mg/L (n = 36). No drug-related adverse events were shown to have a causal association with azithromycin therapy.
Conclusions: Our study showed the clinical benefits of early target attainment of azithromycin therapy. A target trough concentration of 0.25 mg/L in the first 24-48 h of hospitalization was required to ensure better antibacterial efficacy.

PMID: 30060209 [PubMed - as supplied by publisher]

Sex-Dimorphic and Sex Hormone-Dependent Role of Steroid Sulfatase in Adipose Inflammation and Energy Homeostasis.

Endocrinology. 2018 Jul 27;:

Authors: Bi Y, Jiang M, Guo W, Guan X, Xu M, Ren S, Yang D, Gaikwad NW, Selcer KW, Xie W

Abstract
Steroid sulfatase (STS), a desulfating enzyme that converts steroid sulfates to hormonally active steroids, plays an important role in the homeostasis of sex hormones. STS is expressed in the adipose tissue of both male and female mice, but the role of STS in the development and function of adipose tissue remains largely unknown. In this report, we first showed that the adipose expression of Sts was induced in the high-fat diet (HFD) and ob/ob models of obesity and type 2 diabetes. Transgenic overexpression of the human STS in the adipose tissue of male mice exacerbated the HFD induced metabolic phenotypes, including increased body weight gain and fat mass, and worsened insulin sensitivity, glucose tolerance and energy expenditure, which were accounted for by adipocyte hypertrophy, increased adipose inflammation, and dysregulation of adipogenesis. The metabolic harm of the STS transgene appeared to have resulted from increased androgen activity in the adipose tissue, and castration abolished most of the phenotypes. Interestingly, the transgenic effects were sex-specific, because the HFD-fed female STS transgenic mice exhibited improved metabolic functions, which were associated with attenuated adipose inflammation. The metabolic benefit of the STS transgene in female mice was accounted for by increased estrogenic activity in the adipose tissue, whereas such benefit was abolished upon ovariectomy. Our results revealed an essential role of the adipose STS in energy homeostasis in sex- and sex hormone-dependent manner. The adipose STS may represent a novel therapeutic target for the management of obesity and type 2 diabetes.

PMID: 30060148 [PubMed - as supplied by publisher]

Implementation of Pharmacogenetics at Cincinnati Children's Hospital Medical Center: Lessons Learned Over 14 Years of Personalizing Medicine.

Clin Pharmacol Ther. 2018 Jul 29;:

Authors: Ramsey LB, Prows CA, Zhang K, Saldaña SN, Sorter MT, Pestian JP, Wenstrup RJ, Vinks AA, Glauser TA

PMID: 30058217 [PubMed - as supplied by publisher]

Using Stepwise Pharmacogenomics and Proteomics to Predict Hepatitis C Treatment Response in Difficult to Treat Patient Populations.

Proteomics Clin Appl. 2018 Jul 30;:e1800006

Authors: Naggie S, Clement M, Lusk S, Osinusi A, Himmel T, Lucas JE, Thompson WJ, Dubois L, Moseley MA, Clark PJ, Kottilil S, Patel K

Abstract
PURPOSE: In the interferon era of hepatitis C virus (HCV) therapies, genotype/subtype, cirrhosis, prior treatment failure, sex, and race predicted relapse. Our objective was to validate a targeted proteomics platform of 17 peptides to predict sustained virologic response (SVR).
EXPERIMENTAL DESIGN: Stored plasma from three, open-label, trials of HIV/HCV co-infected subjects receiving interferon-containing regimens was identified. LC-MS/MS was used to quantitate the peptides directly from plasma, and IL28B genotyping was completed using stored PBMC. A logistic regression model was built to analyze the probability of SVR using responders and non-responders to interferon-based regimens.
RESULTS: The cohort (N = 35) was predominantly black (51.4%), male (86%), with median age 48 years. Most patients achieved SVR (54%). Using multivariable models, we verified that three human corticosteroid binding globulin (CBG) peptides were predictive of SVR in patients with the unfavorable IL28B genotypes (CT/TT). The model performed better than IL28B alone, with an AUC of 0.870.
CONCLUSIONS AND CLINICAL RELEVANCE: In HIV/HCV co-infected patients, we identified three human CBG peptides that accurately predict treatment response with interferon-based therapy. This study suggests that a stepwise approach combining a genetic predictor followed by targeted proteomics can improve the accuracy of clinical decision-making. This article is protected by copyright. All rights reserved.

PMID: 30058111 [PubMed - as supplied by publisher]

Long-term cardiovascular complications in stage I seminoma patients.

Clin Transl Oncol. 2017 Nov;19(11):1400-1408

Authors: Terbuch A, Posch F, Annerer LM, Bauernhofer T, Pichler M, Szkandera J, Hutterer GC, Pummer K, Partl R, Kapp KS, Stöger H, Gerger A, Stotz M

Abstract
PURPOSE: The cure rate of stage I seminoma patients is close to 100% and so the recent focus of clinical research has shifted onto the prevention of treatment-related complications. We assessed long-term cardiovascular complications and identified risk factors for cardiovascular events (CVEs) in stage I seminoma patients.
METHODS: This retrospective cohort study included 406 consecutive stage I seminoma patients. Primary endpoint was CVE rate.
RESULTS: During a median follow-up of 8.6 years, we observed 23 CVEs in 406 patients [10-year CVE risk 5.6% (95% CI 3.2 to 8.8)]. In univariable competing risk analysis, higher age, positive smoking status, history of diabetes and hypertension were significantly associated with the occurrence of CVE. In multi-state analysis, new onset of diabetes, hypertension and hyperlipidemia during follow-up predicted for an excessively increased CVE risk. In multivariable analysis adjusting for age and smoking, the development of hypertension and hyperlipidemia after tumor-specific treatment prevailed as risk factors for CVE. Regarding adjuvant treatment modalities, patients receiving adjuvant radiotherapy had a significantly higher probability of CVE than patients receiving adjuvant carboplatin [16% vs. 0%; risk difference (RD) = 16%, 95% CI 6 to 25%, p = 0.001]. This difference prevailed after adjusting for age, follow-up-time, diabetes, hypertension and smoking (RD = 11%, 95% CI 1 to 20%, p = 0.025).
CONCLUSION: We identified a panel of baseline risk factors and dynamically, occurring predictors of CVE in stage I seminoma patients. This information may be used for targeting comorbidity management in these patients. The observed association of adjuvant radiotherapy with higher CVE risk warrants further investigation.

PMID: 28852960 [PubMed - indexed for MEDLINE]

Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome: Analysis from the TRACER trial.

Blood Cells Mol Dis. 2018 Jul 21;:

Authors: Tricoci P, Neely M, Whitley MJ, Edelstein LC, Simon LM, Shaw C, Fortina P, Moliterno DJ, Armstrong PW, Aylward P, White H, Van de Werf F, Jennings LK, Wallentin L, Held C, Harrington RA, Mahaffey KW, Bray PF

Abstract
Variation in platelet response to thrombin may affect the safety and efficacy of PAR antagonism. The Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the protease-activated receptor (PAR) 4 gene is associated with higher platelet aggregation compared to the Ala120 variant. We investigated the relationship between the rs773902 SNP with major bleeding and ischemic events, safety, and efficacy of PAR1 inhibition in 6177 NSTE ACS patients in the TRACER trial. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant. The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02-0.92] P = 0.042). No significant differences were observed in the ischemic outcomes. The excess in bleeding observed with PAR1 inhibition was attenuated in patients with the Thr120 variant, but the interactions were not statistically significant. In summary, lower major bleeding rates were observed in the overall TRACER cohort with the hyperreactive PAR4 Thr120 variant. The increase in bleeding with vorapaxar was attenuated with the Thr120 variant, but we could not demonstrate an interaction with PAR1 inhibition. These findings warrant further exploration, including those of African ancestry where the A allele (Thr120) frequency is ~65%.

PMID: 30055940 [PubMed - as supplied by publisher]

IL-6 gene polymorphism is associated with protein serum level and disease activity in Polish patients with rheumatoid arthritis.

HLA. 2018 Jul 27;:

Authors: Wielińska J, Dratwa M, Świerkot J, Korman L, Iwaszko M, Wysoczańska B, Bogunia-Kubik K

Abstract
IL-6 is a pro-inflammatory cytokine involved in development of rheumatoid arthritis (RA). The present study aimed to determine the possible association of the IL6 (rs1800795, G>C) polymorphism with RA susceptibility, disease progression and protein serum levels. Distribution of IL6 alleles and genotypes was similar in RA patients and controls. As expected, patients before induction of anti-TNF agents had significantly higher IL-6 levels as compared to controls (p=0.002). The CC homozygous patients were characterized with the highest average concentrations of this pro-inflammatory cytokine before treatment (p=0.028) and they also more frequently presented with more active disease (p=0.048). These results imply that the IL6 rs1800795 CC homozygosity may play a rather unfavourable role in RA. This article is protected by copyright. All rights reserved.

PMID: 30054992 [PubMed - as supplied by publisher]

Prognostic impact of residual HPV ctDNA detection after chemoradiotherapy for anal squamous cell carcinoma.

Clin Cancer Res. 2018 Jul 27;:

Authors: Cabel L, Jeannot E, Bièche I, Vacher S, Callens C, Bazire L, Morel A, Bernard-Tessier A, Chemlali W, Schnitzler A, Lièvre A, Otz J, Minsat M, Vincent-Salomon A, Pierga JY, Buecher B, Mariani P, Proudhon C, Bidard FC, Cacheux W

Abstract
PURPOSE: Chemoradiotherapy (CRT) is the current standard of care for patients diagnosed with locally advanced anal squamous cell carcinoma (ASCC), but some patients develop local and/or distant relapse during follow-up. The present study was designed to monitor HPV circulating tumor DNA (ctDNA) levels during CRT in patients with ASCC.
EXPERIMENTAL DESIGN: We analyzed samples from patients with HPV16- or HPV18-positive locally advanced ASCC. Blood samples were collected before and after CRT. HPV16 or HPV18 ctDNA detection was performed by droplet digital-PCR.
RESULTS: HPV ctDNA was detected before CRT in 29 of 33 patients with stage II-III ASCC (sensitivity: 88%, 95%CI=[72-95]); ctDNA positivity rate was associated with tumor stage (64% and 100% in stage II and III, respectively; p=0.008). Among ctDNA-positive patients at baseline, ctDNA levels were higher in N+ than in N- tumors (median 85 copies/ml, range (8-9333) vs 32 copies/ml, range (3-1350); p=0.03). ctDNA detection at baseline had no significant prognostic impact. After CRT, 3 of 18 (17%) patients displayed residual detectable HPV ctDNA; ctDNA detection after CRT was strongly associated with shorter disease-free survival (p<0.0001).
CONCLUSIONS: This is the first proof of concept study assessing the prognostic value of ctDNA after CRT in locally advanced ASCC. In most patients, HPV ctDNA can be detected before CRT and becomes undetectable during CRT. In the present study, we show that residual ctDNA levels after CRT are associated with very poor outcome.

PMID: 30054279 [PubMed - as supplied by publisher]

The march of pluripotent stem cells in cardiovascular regenerative medicine.

Stem Cell Res Ther. 2018 Jul 27;9(1):201

Authors: Abou-Saleh H, Zouein FA, El-Yazbi A, Sanoudou D, Raynaud C, Rao C, Pintus G, Dehaini H, Eid AH

Abstract
Cardiovascular disease (CVD) continues to be the leading cause of global morbidity and mortality. Heart failure remains a major contributor to this mortality. Despite major therapeutic advances over the past decades, a better understanding of molecular and cellular mechanisms of CVD as well as improved therapeutic strategies for the management or treatment of heart failure are increasingly needed. Loss of myocardium is a major driver of heart failure. An attractive approach that appears to provide promising results in reducing cardiac degeneration is stem cell therapy (SCT). In this review, we describe different types of stem cells, including embryonic and adult stem cells, and we provide a detailed discussion of the properties of induced pluripotent stem cells (iPSCs). We also present and critically discuss the key methods used for converting somatic cells to pluripotent cells and iPSCs to cardiomyocytes (CMs), along with their advantages and limitations. Integrating and non-integrating reprogramming methods as well as characterization of iPSCs and iPSC-derived CMs are discussed. Furthermore, we critically present various methods of differentiating iPSCs to CMs. The value of iPSC-CMs in regenerative medicine as well as myocardial disease modeling and cardiac regeneration are emphasized.

PMID: 30053890 [PubMed - in process]