Treatment of advanced non-small-cell lung cancer: The 2019 AIOM (Italian Association of Medical Oncology) clinical practice guidelines.

Crit Rev Oncol Hematol. 2019 Dec 28;146:102858

Authors: Passiglia F, Pilotto S, Facchinetti F, Bertolaccini L, Del Re M, Ferrara R, Franchina T, Malapelle U, Menis J, Passaro A, Ramella S, Rossi G, Trisolini R, Novello S

Abstract
The Italian Association of Medical Oncology (AIOM) has developed clinical practice guidelines for the treatment of patients with advanced non-small cell lung cancer (NSCLC). In the current paper a panel of AIOM experts in the field of thoracic malignancies discussed the available scientific evidences, with the final aim of providing a summary of clinical recommendations, which may guide physicians in their current practice.

PMID: 31918343 [PubMed - as supplied by publisher]

Exosomes in Cancer: Circulating Immune-Related Biomarkers.

Biomed Res Int. 2019;2019:1628029

Authors: Głuszko A, Szczepański MJ, Ludwig N, Mirza SM, Olejarz W

Abstract
Exosomes, the smallest vesicles (30-100 nm) among multivesicular bodies, are released by all body cells including tumor cells. The cargo they transfer plays an important role in intercellular communication. Tumor-derived exosomes (TEXs) maintain interactions between cancer cells and the microenvironment. Emerging evidence suggests that tumor cells release a large number of exosomes, which may not only influence proximal tumor cells and stromal cells in the local microenvironment but can also exert systemic effects as they are circulating in the blood. TEXs have been shown to boost tumor growth promote progression and metastatic spread via suppression or modification of the immune response towards cancer cells, regulation of tumor neo-angiogenesis, pre-metastatic niche formation, and therapy resistance. In addition, recent studies in patients with cancer suggest that TEXs could serve as tumor biomarker reflecting partially the genetic and molecular content of the parent cancer cell (i.e., as a so-called "liquid biopsy"). Furthermore, recent studies have demonstrated that exosomes may have immunotherapeutic applications, or can act as a drug delivery system for targeted therapies with drugs and biomolecules.

PMID: 31915681 [PubMed - in process]

Motor cortex excitability and inhibitory imbalance in autism spectrum disorder assessed with transcranial magnetic stimulation: a systematic review.

Transl Psychiatry. 2019 03 07;9(1):110

Authors: Masuda F, Nakajima S, Miyazaki T, Yoshida K, Tsugawa S, Wada M, Ogyu K, Croarkin PE, Blumberger DM, Daskalakis ZJ, Mimura M, Noda Y

Abstract
Cortical excitation/inhibition (E/I) imbalances contribute to various clinical symptoms observed in autism spectrum disorder (ASD). However, the detailed pathophysiologic underpinning of E/I imbalance remains uncertain. Transcranial magnetic stimulation (TMS) motor-evoked potentials (MEP) are a non-invasive tool for examining cortical inhibition in ASD. Here, we conducted a systematic review on TMS neurophysiology in motor cortex (M1) such as MEPs and short-interval intracortical inhibition (SICI) between individuals with ASD and controls. Out of 538 initial records, we identified six articles. Five studies measured MEP, where four studies measured SICI. There were no differences in MEP amplitudes between the two groups, whereas SICI was likely to be reduced in individuals with ASD compared with controls. Notably, SICI largely reflects GABA(A) receptor-mediated function. Conversely, other magnetic resonance spectroscopy and postmortem methodologies assess GABA levels. The present review demonstrated that there may be neurophysiological deficits in GABA receptor-mediated function in ASD. In conclusion, reduced GABAergic function in the neural circuits could underlie the E/I imbalance in ASD, which may be related to the pathophysiology of clinical symptoms of ASD. Therefore, a novel treatment that targets the neural circuits related to GABA(A) receptor-mediated function in regions involved in the pathophysiology of ASD may be promising.

PMID: 30846682 [PubMed - indexed for MEDLINE]

No association between ATP-binding cassette transporter G2 rs2231142 (Q141K) and urate-lowering response to febuxostat.

Rheumatology (Oxford). 2019 03 01;58(3):547-548

Authors: Stamp LK, Topless R, Miner JN, Dalbeth N, Merriman T

PMID: 30597115 [PubMed - indexed for MEDLINE]

Clinical outcome in anti-neutrophil cytoplasmic antibody-associated vasculitis and gene variants of 11β-hydroxysteroid dehydrogenase type 1 and the glucocorticoid receptor.

Rheumatology (Oxford). 2019 03 01;58(3):447-454

Authors: Hessels AC, Tuin J, Sanders JSF, Huitema MG, van Rossum EFC, Koper JW, van Beek AP, Stegeman CA, Rutgers A

Abstract
OBJECTIVES: We aimed to investigate whether five potential functional haplotypes of the glucocorticoid receptor (GR) gene and a single-nucleotide polymorphism of 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) are associated with clinical outcome in ANCA-associated vasculitis.
METHODS: Patients diagnosed with ANCA-associated vasculitis (n = 241) were genotyped for five polymorphisms of the GR gene and one polymorphism of the HSD11B1 gene. GR gene haplotypes were predicted based on genotyping results. Relapse-free survival, mortality, renal survival, metabolic adverse events and infections were compared between carriers and non-carriers of GR haplotypes and the HSD11B1 genotype.
RESULTS: Carriers of haplotype 4 (ER22/23EK + 9β+TthIII1) of GR had a significantly higher 5-year mortality risk [hazard ratio (HR) 4.5 (95% CI 1.6, 12.8)] and had a higher risk of developing end-stage renal disease [HR 7.4 (95% CI 1.9, 28.7)]. Carriers of a minor variant of HSD11B1 more frequently experienced relapse [HR 2.5 (95% CI 1.5, 4.1)] except if they also carried haplotype 1 (BclI) of GR. Homozygous carriers of haplotype 1 had a higher risk of developing dyslipidaemia [HR 4.1 (95% CI 1.8, 9.6)]. The occurrence of infections did not differ between GR haplotypes and HSD11B1 genotypes.
CONCLUSION: Haplotypes 1 and 4 of GR and a polymorphism of the HSD11B1 gene were associated with clinically relevant inflammatory and metabolic outcomes in ANCA-associated vasculitis.

PMID: 30445609 [PubMed - indexed for MEDLINE]

Tumour immune cell infiltration and survival after platinum-based chemotherapy in high-grade serous ovarian cancer subtypes: A gene expression-based computational study.

EBioMedicine. 2020 Jan 03;51:102602

Authors: Liu R, Hu R, Zeng Y, Zhang W, Zhou HH

Abstract
BACKGROUND: Increasing evidence supports that the immune infiltration of tumours is associated with prognosis. Here, we sought to assess the relevance of the cellular composition of the immune infiltrate to survival after platinum-based chemotherapy amongst patients with high-grade serous ovarian cancer and evaluate these effects by molecular subtype.
METHODS: We searched publicly available databases and identified 13 studies with more than 2000 patients. We estimated the proportions of 22 immune cell subsets by using a computational approach (CIBERSORT). Then, we investigated the associations between each immune cell subset and progression-free survival (PFS) and overall survival (OS), with cellular proportions modelled as quartiles.
FINDINGS: A high fraction of M1 [hazard ratio (HR) = 0.92, 95% confidence interval (CI) = 0.86-0.99] and M0 (HR = 0.93, 95% CI = 0.87-0.99) macrophages emerged as the most closely associated with favourable OS. Neutrophils were associated with poor OS (HR = 1.06, 95% CI = 1.00-1.13) and PFS (HR = 1.10, 95% CI = 1.02-1.13). Amongst the immunoreactive tumours, the M0 macrophages and the CD8+ T cells were associated with improved OS, whereas the M2 macrophages conferred worse OS. Interestingly, PD-1 was associated with good OS (HR=0.89, 95% CI = 0.80-1.00) and PFS (HR=0.89, 95% CI = 0.79-1.01) in this subtype. Four subgroups of tumours with distinct survival patterns were identified using immune cell proportions with unsupervised clustering.
INTERPRETATION: Further investigations of the quantitative cellular immune infiltrations in tumours may contribute to therapeutic advances.

PMID: 31911269 [PubMed - as supplied by publisher]

Should UK primary care be an early adopter of genomic medicine?

Br J Gen Pract. 2019 Jul;69(684):330-331

Authors: Dickenson D, Rafi I, Spicer J, Papanikitas A

PMID: 31249073 [PubMed - indexed for MEDLINE]

Pediatric Acute Lymphoblastic Leukemia, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw. 2020 Jan;18(1):81-112

Authors: Brown P, Inaba H, Annesley C, Beck J, Colace S, Dallas M, DeSantes K, Kelly K, Kitko C, Lacayo N, Larrier N, Maese L, Mahadeo K, Nanda R, Nardi V, Rodriguez V, Rossoff J, Schuettpelz L, Silverman L, Sun J, Sun W, Teachey D, Wong V, Yanik G, Johnson-Chilla A, Ogba N

Abstract
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Advancements in technology that enhance our understanding of the biology of the disease, risk-adapted therapy, and enhanced supportive care have contributed to improved survival rates. However, additional clinical management is needed to improve outcomes for patients classified as high risk at presentation (eg, T-ALL, infant ALL) and who experience relapse. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric ALL provide recommendations on the workup, diagnostic evaluation, and treatment of the disease, including guidance on supportive care, hematopoietic stem cell transplantation, and pharmacogenomics. This portion of the NCCN Guidelines focuses on the frontline and relapsed/refractory management of pediatric ALL.

PMID: 31910389 [PubMed - in process]

A Scoping Review of the Evidence Behind CYP2D6 Inhibitor Classifications.

Clin Pharmacol Ther. 2020 Jan 07;:

Authors: Cicali EJ, Smith DM, Duong BQ, Kovar LG, Cavallari LH, Johnson JA

Abstract
The FDA lists 22 medications as clinical inhibitors of CYP2D6, with classifications of strong, moderate, and weak. It is accepted that strong inhibitors result in nearly null enzymatic activity, but reduction caused by moderate and weak inhibitors is less well characterized. The objective was to identify if the classification of currently listed FDA moderate and weak inhibitors is supported by publicly available primary literature. We conducted a literature search and reviewed product labels (PLs) for AUC-fold changes caused by inhibitors in humans and identified 89 inhibitor-substrate pairs. Observed AUC-fold change of the substrate was used to create an observed inhibitor classification per FDA-defined AUC-fold change thresholds. We then compared the observed inhibitor classification with the classification listed in the FDA Table of Inhibitors. We found 62% of the inhibitors within the pairs matched the listed FDA classification. We explored reasons for discordance and suggest modifications to the FDA table of clinical inhibitors for cimetidine, desvenlafaxine, and fluvoxamine.

PMID: 31910286 [PubMed - as supplied by publisher]

Prevalence of overweight and obesity in children with X-linked hypophosphatemia.

Endocr Connect. 2020 Jan 01;:

Authors: Zhukouskaya V, Rothenbuhler A, Colao AA, Di Somma C, Kamenický P, Trabado S, Prie D, Audrain C, Barosi A, Kyheng C, Lambert AS, Linglart A

Abstract
BACKGROUND/AIM: X-linked hypophosphatemia (XLH) is a rare disease characterized by low phosphate levels. Scientific evidence points to link between hypophosphatemia and obesity in general population. The aim of our longitudinal observational study was to investigate the prevalence of obesity and associated factors in a large cohort of children with XLH.
PATIENTS/METHODS: We studied 172 XLH-children 5-20 years of age (113 girls /59 boys). Anthropometric parameters (weight, height, BMI) were collected at birth and during follow-up at mean ages of 5.3-8.2-11.3-15.9 years (groups 1-2-3-4, respectively). In each group, subjects were classified based on International Obesity Taskforce (IOTF) cut off values of BMI for age and sex as overweight or obese (IOTF 25-30 or ≥30 kg/m2, respectively).
RESULTS: In each age-group, almost 1/3 of XLH-patients were classified as overweight or obese (29.4%, 28.7%, 27.5% and 36.7% in groups 1-2-3-4, respectively). Children without a XLH-family history had higher BMI-IOTF at every point of follow-up, compared to those with positive XLH-family history. Similarly, higher BMI-IOTF was significantly associated with treatment duration (23.3±4.4 vs 23.8±3.8 vs 25.2±4.5 kg/m2, for subjects with treatment duration of <5, 5-10 and >10 years, respectively, p for trend=0.025). Multiple regression analysis confirmed an association of treatment duration and lack of XLH-family history with higher BMI-IOTF.
CONCLUSION: 1/3 of XLH-children have phenotypically unfavourable metabolic profile expressed as increased prevalence of overweight/obesity. Both the lack of XLH family history and duration of treatment increase the risk of higher BMI-IOTF. BMI should be carefully monitored in children and later adults, with XLH.

PMID: 31910157 [PubMed - as supplied by publisher]

A New Way to Discover IRESs in Pathology or Stress Conditions? Harnessing Latest High-Throughput Technologies.

Bioessays. 2020 Jan 07;:e1900180

Authors: Wang LY, Cui JJ, Guo CX, Yin JY

Abstract
The cellular internal ribosomal entry site (IRES) is one of the most important elements to mediate cap-independent translational initiation, especially under conditions of stress and pathology. However, a high-throughput method to discover IRESs in these conditions is still lacking. Here, a possible way IRES long-read sequencing based on the latest high-throughput technologies is proposed to solve this problem. Based on this design, diversity and integrity of the transcriptome from original samples can be kept. The micro-environment that stimulates or inhibits IRES activity can also be mimicked. By using long read-length sequencing technology, additional experiments that are essential for ruling out the cryptic promoters or splicing events in routine IRES identification processes can be circumvented. It is hoped that this proposed methodology may be adopted for IRES element discovery, hence uncovering the full extent of the role of IRESs in disease, development, and stress.

PMID: 31909834 [PubMed - as supplied by publisher]

KRCC1: A potential therapeutic target in ovarian cancer.

FASEB J. 2019 Dec 23;:

Authors: Dwivedi SKD, Shameer K, Dey A, Mustafi SB, Xiong X, Bhattacharya U, Neizer-Ashun F, Rao G, Wang Y, Ivan C, Yang D, Dudley JT, Xu C, Wren JD, Mukherjee P, Bhattacharya R

Abstract
Using a systems biology approach to prioritize potential points of intervention in ovarian cancer, we identified the lysine rich coiled-coil 1 (KRCC1), as a potential target. High-grade serous ovarian cancer patient tumors and cells express significantly higher levels of KRCC1 which correlates with poor overall survival and chemoresistance. We demonstrate that KRCC1 is predominantly present in the chromatin-bound nuclear fraction, interacts with HDAC1, HDAC2, and with the serine-threonine phosphatase PP1CC. Silencing KRCC1 inhibits cellular plasticity, invasive properties, and potentiates apoptosis resulting in reduced tumor growth. These phenotypes are associated with increased acetylation of histones and with increased phosphorylation of H2AX and CHK1, suggesting the modulation of transcription and DNA damage that may be mediated by the action of HDAC and PP1CC, respectively. Hence, we address an urgent need to develop new targets in cancer.

PMID: 31908025 [PubMed - as supplied by publisher]

[Too early for pharmacogenetics in psychiatric practice? Implementation is in full swing].

Tijdschr Psychiatr. 2019;61(10):678-680

Authors: van Westrhenen R, Bet PM, van Weelden M, van Schaik RHN

PMID: 31907910 [PubMed - in process]

"Bridging the Gap" Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era.

Int J Mol Sci. 2019 Dec 31;21(1):

Authors: Gemmati D, Varani K, Bramanti B, Piva R, Bonaccorsi G, Trentini A, Manfrinato MC, Tisato V, Carè A, Bellini T

Abstract
. Gender medicine is the first step of personalized medicine and patient-centred care, an essential development to achieve the standard goal of a holistic approach to patients and diseases. By addressing the interrelation and integration of biological markers (i.e., sex) with indicators of psychological/cultural behaviour (i.e., gender), gender medicine represents the crucial assumption for achieving the personalized health-care required in the third millennium. However, 'sex' and 'gender' are often misused as synonyms, leading to frequent misunderstandings in those who are not deeply involved in the field. Overall, we have to face the evidence that biological, genetic, epigenetic, psycho-social, cultural, and environmental factors mutually interact in defining sex/gender differences, and at the same time in establishing potential unwanted sex/gender disparities. Prioritizing the role of sex/gender in physiological and pathological processes is crucial in terms of efficient prevention, clinical signs' identification, prognosis definition, and therapy optimization. In this regard, the omics-approach has become a powerful tool to identify sex/gender-specific disease markers, with potential benefits also in terms of socio-psychological wellbeing for each individual, and cost-effectiveness for National Healthcare systems. "Being a male or being a female" is indeed important from a health point of view and it is no longer possible to avoid "sex and gender lens" when approaching patients. Accordingly, personalized healthcare must be based on evidence from targeted research studies aimed at understanding how sex and gender influence health across the entire life span. The rapid development of genetic tools in the molecular medicine approaches and their impact in healthcare is an example of highly specialized applications that have moved from specialists to primary care providers (e.g., pharmacogenetic and pharmacogenomic applications in routine medical practice). Gender medicine needs to follow the same path and become an established medical approach. To face the genetic, molecular and pharmacological bases of the existing sex/gender gap by means of omics approaches will pave the way to the discovery and identification of novel drug-targets/therapeutic protocols, personalized laboratory tests and diagnostic procedures (sex/gender-omics). In this scenario, the aim of the present review is not to simply resume the state-of-the-art in the field, rather an opportunity to gain insights into gender medicine, spanning from molecular up to social and psychological stances. The description and critical discussion of some key selected multidisciplinary topics considered as paradigmatic of sex/gender differences and sex/gender inequalities will allow to draft and design strategies useful to fill the existing gap and move forward.

PMID: 31906252 [PubMed - in process]

Relationship between genetic variation in the α2A-adrenergic receptor and the cardiovascular effects of dexmedetomidine in the Chinese Han population.

J Zhejiang Univ Sci B. 2019 Jul;20(7):598-604

Authors: Zhu SJ, Wang KR, Zhang XX, Zhu SM

Abstract
There are differences in individual cardiovascular responses to the administration of dexmedetomidine, a highly selective α2A-adrenergic receptor (ADRA2A) agonist. The aim of this study was to investigate ADRA2A gene polymorphisms in the Chinese Han population and their association with the cardiovascular response to intravenous dexmedetomidine infusion. Sixty elective surgery patients of Chinese Han nationality were administered 1 µg/kg dexmedetomidine intravenously over 10 min as a premedication. ADRA2A C-1291G and A1780G polymorphism status was determined in these patients, and their relationships to changes in blood pressure and heart rate after dexmedetomidine administration were analyzed. There were neither significant differences in systolic or diastolic blood pressure changes in individuals with different A1780G and C-1291G genotypes after dexmedetomidine administration, nor in heart rates among the different A1780G genotypes. However, there were significant differences in changes in heart rates in patients with different C-1291G genotypes. There were no significant differences in the sedative effects of dexmedetomidine among different A1780G and C-1291G genotypes. Logistic regression revealed that the C-1291G polymorphism was associated with differential decreases in heart rate after intravenous infusion of dexmedetomidine. These findings indicate that the ADRA2A C-1291G polymorphism can affect heart rate changes in patients after intravenous infusion of dexmedetomidine.

PMID: 31168973 [PubMed - indexed for MEDLINE]

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Pharmacology of tyrosine kinase inhibitors in chronic myeloid leukemia; a clinician's perspective.

Daru. 2020 Jan 03;:

Authors: Pushpam D, Bakhshi S

Abstract
OBJECTIVE: In this review, we have summarized the pharmacokinetics, pharmacodynamics and adverse effects of imatinib, dasatinib, nilotinib, bosutinib, ponatinib and radotinib with focus on pharmacogenomic studies with clinical end points. We have discussed the key phase 3 trials of tyrosine kinase inhibitors (TKI) comparing with each other, treatment free remission (TFR) and selection of TKI. Upcoming concepts and related trials in the management of chronic myeloid leukemia (CML) along with future directions have been touched upon.
EVIDENCE ACQUISITION: PubMed, Embase, Google, Cochrane library and Medline were searched to identify relevant literature for the review. Clinicaltrial.gov was searched for upcoming data and trials.
RESULTS: There are lot of gap in pharmacokinetics and pharmacodynamics of TKI. Imatinib appears to be the safest TKI. Newer TKI's achieve better achievement of therapeutic milestones, deeper molecular response and less chances of progression of CML compared to imatinib. Newer TKI appears to be better choice for achieving TFR. When the objective is survival, imatinib is still the TKI of choice. Primary prophylaxis with antiplatelet drugs for TKI having cardiovascular and thromboembolic side effects should be considered.
CONCLUSION: Pharmacogenetic data of TKI is still immature to guide in therapeutic decision making in clinical practice. There is need for further research in pharmacology and pharmacogenomics of newer TKI's. Randomized controlled trials are required to decide the optimum TKI for TFR. Safe and effective TKI for targeting T315I mutation, CML accelerated phase and blast crisis are an active area of research.

PMID: 31900888 [PubMed - as supplied by publisher]

Status Epilepticus: The Slow and Agonizing Death of Phenytoin.

J Pediatr Pharmacol Ther. 2020 Jan-Feb;25(1):4-6

Authors: Hall EA, Wheless JW, Phelps SJ

Abstract
Since its introduction in 1950, phenytoin (PHT) has been the premier parenteral anticonvulsant used in the management of generalized convulsive status epileptics (GCSE) that is refractory to benzodiazepines. Without question, its arrival was vital to the care of patients with acute seizures and was a welcomed alternative to paraldehyde and phenobarbital. However, after more than half a century of use, there continues to be insufficient evidence-based data to support its efficacy over other anticonvulsants as a first-line agent in pediatric or adult patients with GCSE. This coupled with its narrow mechanism of action, complex pharmacokinetics and pharmacogenomics, drug-drug interactions, unique adverse effects, and formulation issues that make administration difficult mandates that PHT be replaced by safer and superiorly effective anticonvulsants for the treatment of GCSE when benzodiazepines are ineffective. We believe that levetiracetam should become the preferred agent for seizures unresponsive to or recurring after treatment with a benzodiazepine as it is at least equally effective to PHT and has several important advantages. PHT has overstayed its welcome and it is simply time for it to exit the realm of acute seizure management as a first-line agent for benzodiazepine-refractory GCSE.

PMID: 31897070 [PubMed]

NF-kB signaling in cardiomyocytes is inhibited by sevoflurane and promoted by propofol.

FEBS Open Bio. 2020 Jan 03;:

Authors: Oda-Kawashima K, Sedukhina AS, Okamoto N, Lytvyn M, Minagawa K, Iwata T, Kumai T, Sato E, Inada E, Yamaura A, Sakamoto M, Roche-Molina M, Bernal JA, Sato K

Abstract
Both inhalational and intravenous anesthetics affect myocardial remodeling, but the precise effect of each anesthetic on molecular signaling in myocardial remodeling is unknown. Here, we performed in silico analysis to investigate signaling alterations in cardiomyocytes induced by inhalational (sevoflurane) and intravenous (propofol) anesthetics. Bioinformatics analysis revealed that NF-kB signaling was inhibited by sevoflurane and promoted by propofol. Moreover, nuclear accumulation of p65 and transcription of NF-kB-regulated genes were suppressed in sevoflurane-administered mice, suggesting that sevoflurane inhibits the NF-kB signaling pathway. Our data demonstrate that NF-kB signaling is inhibited by sevoflurane and promoted by propofol. As NF-kB signaling plays an important role in myocardial remodeling, our results suggest that anesthetics may affect myocardial remodeling through NF-kB.

PMID: 31898867 [PubMed - as supplied by publisher]

Valproic Acid Decreases Endothelial Colony Forming Cells Differentiation and Induces Endothelial-to-Mesenchymal Transition-like Process.

Stem Cell Rev Rep. 2020 Jan 02;:

Authors: Nevo N, Lecourt S, Bièche I, Kucia M, Cras A, Blandinieres A, Vacher S, Gendron N, Guerin CL, Ratajczak MZ, Smadja DM

Abstract
Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor is a widely used anticonvulsant drug. VPA is also under clinical evaluation to be employed in anticancer therapy, as an antithrombotic agent or a molecule to be used in the stem cells expansion protocols. Since endothelial colony forming cells (ECFC) has been identified as the human postnatal vasculogenic cells involved in thrombotic disorders and serve as a promising source of immature cell for vascular repair, objectives of the present study were to determine how VPA contributes to ECFC commitment and their angiogenic properties. We examined the effect of VPA on ECFC obtained from cord blood by evaluating colony number, proliferation, migration and their sprouting ability in vitro, as well as their in vivo vasculogenic properties. VPA inhibited endothelial differentiation potential from of cord blood derived stem cells associated with decreased proliferation and sprouting activity of cultured ECFC. VPA treatment significantly decreased the vessel-forming ability of ECFC transplanted together with mesenchymal stem cells (MSC) in Matrigel implants in nude mice model. Surprisingly, a microscopic evaluation revealed that VPA induces marked morphological changes from a cobblestone-like EC morphology to enlarged spindle shaped morphology of ECFC. RT-qPCR and a CD31/CD90 flow cytometry analysis confirmed a phenotypic switch of VPA-treated ECFC to mesenchymal-like phenotype. In conclusion, the pan-HDAC inhibitor VPA described for expansion of hematopoietic stem cells and very small embryonic like stem cells cannot be successfully employed for differentiation of endothelial lineage committed ECFC into functional endothelial cells. Our data also suggest that VPA based therapeutics may induce endothelial dysfunction associated with fibrosis that might induce thrombosis recurrence or venous insufficiency.

PMID: 31898801 [PubMed - as supplied by publisher]