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Murine models based on acute myeloid leukemia-initiating stem cells xenografting

World Journal of Stem Cells 2018年第6期10卷 57-65页

作者： cristina Mambet Mihaela Chivu-Economescu Lilia Matei Laura Georgiana Necula Denisa Laura Dragu Coralia Bleotu carmen cristina diaconu Cellular and Molecular Pathology Department Stefan S. Nicolau Institute of Virology Nicolae Cajal Institute Titu Maiorescu University

Acute myeloid leukemia(AML) is an aggressive malignant disease defined by abnormal expansion of myeloid blasts. Despite recent advances in understanding AML pathogenesis and identifying their molecular subtypes based on somatic mutations, AML is still characterized by poor outcomes, with a 5-year survival rate of only 30%-40%, the majority of the patients dying due to AML relapse. Leukemia stem cells(LSC) are considered to be at the root of chemotherapeutic resistance and AML relapse. Although numerous studies have tried to better characterize LSCs in terms of surface and molecular markers, a specific marker of LSC has not been found, and still the most universally accepted phenotypic signature remains the surface antigens CD34+CD38- that is shared with normal hematopoietic stem cells. Animal models provides the means to investigate the factors responsible for leukemic transformation, the intrinsic differences between secondary post-myeloproliferative neoplasm AML and de novo AML, especially the signaling pathways involved in inflammation and hematopoiesis. However, AML proved to be one of the hematological malignancies that is difficult to engraft even in the most immunodeficient mice strains, and numerous ongoing attempts are focused to develop "humanized mice" that can support the engraftment of LSC. This present review is aiming to in-troduce the field of AML pathogenesis and the concept of LSC, to present the current knowledge on leukemic blasts surface markers and recent attempts to develop best AML animal models.

关键词： Acute myeloid leukemia Leukemia-initiating stem cells Antigen markers Murine models Xenografts

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Gastrointestinal cancer stem cells as targets for innovative immunotherapy

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World Journal of Gastroenterology 2020年第14期26卷 1580-1593页

作者： Mihaela Chivu-Economescu Laura G Necula Lilia Matei Denisa Laura Dragu Ana I Neagu Irina Alexiu Coralia Bleotu carmen cristina diaconu Department of Cellular and Molecular Pathology Stefan S.Nicolau Institute of VirologyBucharest 030304Romania Nicolae Cajal Institute Titu Maiorescu UniversityBucharest 040441Romania

The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized.Gastrointestinal cancer stem cells(GCSCs)are considered to be responsible for tumor initiation,growth,resistance to cytotoxic therapies,recurrence and metastasis due to their unique properties.These properties make the current therapeutic trials against GCSCs ineffective.Moreover,recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system.Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy.This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells,instead of aiming physically destruction of cancer cells through radio-or chemotherapy.New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens,using innate immune cells like the natural killer and T cells,T-cell chimeric antigen receptor technology,dendritic cell vaccine,or immune checkpoint inhibitors.In this respect,better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy.

关键词： Immunotherapy Gastrointestinal cancer Cancer stem cells CAR-T Dendritic cells vaccines Immune checkpoints inhibitors

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Prospective study of hepatitis B and D epidemiology and risk factors in Romania:A 10-year update

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World Journal of Hepatology 2024年第4期16卷 640-649页

作者： Speranta Iacob Liana Gheorghe Mirela Onica Laura Huiban Corina Silvia Pop Ciprian Brisc Roxana Sirli carmen Ester cristina Mihaela Brisc Sorina diaconu Ion Rogoveanu Larisa Sandulescu Deiana Vuletici Anca Trifan Department of Gastroenterology Carol Davila University of Medicine and PharmacyBucharest 050474Romania Department of Gastroenterology and Hepatology Fundeni Clinical InstituteBucharest 022328Romania Department of Gastroenterology Grigore T Popa University of Medicine and PharmacyIasi 700115Romania Institute of Gastroenterology and Hepatology Saint Spiridon County HospitalIasi 700111Romania Department of Gastroenterology and Medical Oncology University Emergency Clinical HospitalBucharest 050098Romania Faculty of Medicine and Pharmacy University of OradeaOradea 410087Romania Department of Gastroenterology Emergency County HospitalOradea 410169Romania Center for Advanced Research in Gastroenterology and Hepatology Department of Gastroenterology and Hepatology“Victor Babeş”University of Medicine and PharmacyTimisoara 300041Romania Department of Gastroenterology and Hepatology TimişCounty Emergency Clinical Hospital"Pius Branzeu"Timisoara 300723Romania Department of Internal Medicine II and Gastroenterology University Emergency Clinical HospitalBucharest 050098Romania Department of Gastroenterology University of Medicine and PharmacyCraiova 200349Romania Department of Cardiology Emergency County HospitalCraiova 200642Romania Department of Gastroenterology Research Center of Gastroenterology and HepatologyUniversity of Medicine and PharmacyCraiova 200349Romania Department of Gastroenterology Emergency County HospitalCraiova 200642Romania Department of Gastroenterology Faculty of MedicineGrigore T Popa University of Medicine and PharmacyIasi 700115Romania

BACKGROUND The global burden of hepatitis D virus(HDV)infection represents a major medical challenge and a public health crisis worldwide.However,there is a lack of accurate data on the epidemiology and risk factors for HDV.Hepatitis B virus(HBV)and HDV coinfection causes the most severe form of viral hepatitis,leading to a higher cumulative incidence of liver-related events compared with HBV monoinfection,including the need for liver transplantation and death.AIM To investigate the epidemiology,natural history,risk factors and clinical management of HBV and HDV coinfection in Romanian patients.METHODS This prospective study was conducted between January and July 2022 in six tertiary gastroenterology and hepatology referral centres in Romania.All consecutive adults admitted for any gastroenterology diagnosis who were HBV-positive were enrolled.Patients with acute hepatitis or incomplete data were excluded.Of the 25390 individuals who presented with any type of gastroenterology diagnosis during the study period,963 met the inclusion criteria.Testing for anti-HDV antibodies and HDV RNA was performed for all participants.Demographic and risk factor data were collected by investigators using medical charts and patient questionnaires.All data were stored in an anonymized online database during the study.RESULTS The prevalence of HBV was 3.8%;among these patients,the prevalence of HBV/HDV coinfection was 33.1%.The median age of the study population was 54.0 years,and it consisted of 55.1%men.A higher prevalence of HBV/HDV coinfection was observed in patients 50–69 years old.Patients with HBV/HDV coinfection were significantly older than those with HBV monoinfection(P=0.03).Multivariate multiple regression analysis identified female gender(P=0.0006),imprisonment(P<0.0001),older age at diagnosis(P=0.01)and sexual contact with persons with known viral hepatitis(P=0.0003)as significant risk factors for HDV.CONCLUSION This study shows that HDV infection among those with HBV remains endemic in Romania and updates our underst

关键词： Epidemiology Hepatitis B Hepatitis D Natural history Risk factors Romania

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Overview of dyslipidemia and metabolic syndrome in myeloproliferative neoplasms

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World Journal of Clinical Oncology 2024年第6期15卷 717-729页

作者： Mihnea-Alexandru Găman Bahadar Singh Srichawla Yong-Feng Chen Poulami Roy Arkadeep Dhali Ahmed Nahian Muhammad Romail Manan Vincent Kipkorir Richard Christian Suteja Lakshmi Venkata Simhachalam Kutikuppala Amelia Maria Găman Camelia cristina diaconu Faculty of Medicine “Carol Davila”University of Medicine and PharmacyBucharest 050474Romania Department of Hematology Center of Hematolog Department of Cellular and Molecular Pathology Stefan S Nicolau Institute of VirologyRomanian AcademyBucharest 030304Romania Department of Neurology University of Massachusetts Chan Medical SchoolWorcesterMA 01655United States Department of Basic Medical Sciences School of Medicine of Taizhou UniversityTaizhou UniversityTaizhou 318000Zhejiang ProvinceChina Department of Medicine North Bengal Medical College and HospitalWest Bengal 734012India Academic Department of Gastroenterology Sheffield Teaching Hospitals NHS Foundation TrustSheffield S57AUUnited Kingdom Lecom at Seton Hill GreensburgPA 15601United States Faculty of Medicine Services HospitalLahore 54000Pakistan Department of Human Anatomy and Physiology University of NairobiNairobi 00100Kenya Faculty of Medicine Udayana UniversityDenpasarBali 80361Indonesia Department of General Surgery Dr.NTR University of Health SciencesVijayawada 520008Andhra PradeshIndia Department of Pathophysiology University of Medicine and Pharmacy of CraiovaCraiova 200349Romania Clinic of Hematology Filantropia City HospitalCraiova 200143Romania Department of Internal Medicine Faculty of Medicine“Carol Davila”University of Medicine and PharmacyBucharest 050474Romania Internal Medicine Clinic Clinical Emergency Hospital of BucharestBucharest 105402Romania

Myeloproliferative neoplasms(MPNs)occur due to the abnormal proliferation of one or more terminal myeloid cell lines in peripheral blood.Subjects suffering from MPNs display a high burden of cardiovascular risk factors,and thrombotic events are often the cause of death in this population of patients.Herein,we provide a brief overview of dyslipidemia and metabolic syndrome and their epidemiology in MPNs and examine the common molecular mechanisms between dyslipidemia,metabolic syndrome,and MPNs,with a special focus on cardio-vascular risk,atherosclerosis,and thrombotic events.Furthermore,we investigate the impact of dyslipidemia and metabolic syndrome on the occurrence and survival of thrombosis in MPN patients,as well as the management of dyslipidemia in MPNs,and the impact of MPN treatment on serum lipid concentrations,particularly as side/adverse effects reported in the context of clinical trials.

关键词： Polycythemia vera Essential thrombocythemia Myelofibrosis Cardiovascular disease Hypercholesterolemia Hypertriglyceridemia Obesity Diabetes Inflammation Oxidative stress

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Acute myocardial infarction in myeloproliferative neoplasms

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World Journal of Cardiology 2023年第11期15卷 571-581页

作者： Muhammad Romail Manan Vincent Kipkorir Iqra Nawaz Maryann Wanjiku Waithaka Bahadar Singh Srichawla Amelia Maria Găman Camelia cristina diaconu Mihnea-Alexandru Găman Services Institute of Medical Sciences Lahore 54000Pakistan Department of Human Anatomy and Physiology University of NairobiNairobi 00100Kenya Quaid-e-Azam Medical College Bahawalpur 63100Pakistan Department of Neurology University of Massachusetts Chan Medical SchoolWorcesterMA 01655United States Department of Pathophysiology University of Medicine and Pharmacy of CraiovaCraiova 200143Romania Clinic of Hematology Filantropia City HospitalCraiova 200143Romania Department of Internal Medicine Faculty of Medicine“Carol Davila”University of Medicine and PharmacyBucharest 050474Romania Internal Medicine Clinic Clinical Emergency Hospital of BucharestBucharest 105402Romania Faculty of Medicine “Carol Davila”University of Medicine and PharmacyBucharest 050474Romania Department of Hematology Center of Hematology and Bone Marrow TransplantationFundeni Clinical InstituteBucharest 022328Romania Department of Cellular and Molecular Pathology Stefan S.Nicolau Institute of VirologyRomanian AcademyBucharest 030304Romania

Myeloproliferative neoplasms(MPNs)are a heterogeneous group of hematologic malignancies characterized by an abnormal proliferation of cells of the myeloid lineage.Affected individuals are at increased risk for cardiovascular and thrombotic events.Myocardial infarction(MI)may be one of the earliest clinical manifestations of MPNs or may be a thrombotic complication that develops during the natural course of the disease.In the present review,we examine the epidemiology,pathogenesis,clinical presentation,and management of MI in MPNs based on the available literature.Moreover,we review potential biomarkers that could mediate the MI-MPNs crosstalk,from classical biochemical tests,e.g.,lactate dehydrogenase,creatine kinase and troponins,to pro-inflammatory cytokines,oxidative stress markers,and clonal hematopoiesis.

关键词： Myeloproliferative neoplasms Polycythemia vera Essential thrombocythemia Myelofibrosis Myocardial infarction Acute coronary syndrome Biomarker Clonal hematopoiesis

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Recent advances in gastric cancer early diagnosis

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World Journal of Gastroenterology 2019年第17期25卷 2029-2044页

作者： Laura Necula Lilia Matei Denisa Dragu Ana I Neagu cristina Mambet Saviana Nedeianu Coralia Bleotu carmen C diaconu Mihaela Chivu-Economescu Department of Cellular and Molecular Pathology Stefan S.Nicolau Institute of Virology Faculty of Medicine Titu Maiorescu University

Gastric cancer(GC) remains an important cause of cancer death worldwide with a high mortality rate due to the fact that the majority of GC cases are diagnosed at an advanced stage when the prognosis is poor and the treatment options are limited. Unfortunately, the existing circulating biomarkers for GC diagnosis and prognosis display low sensitivity and specificity and the GC diagnosis is based only on the invasive procedures such as upper digestive endoscopy. There is a huge need for less invasive or non-invasive tests but also highly specific biomarkers in case of GC. Body fluids such as peripheral blood, urine or saliva,stomach wash/gastric juice could be a source of specific biomarkers, providing important data for screening and diagnosis in GC. This review summarized the recently discovered circulating molecules such as microRNAs, long non-coding RNAs, circular RNAs, which hold the promise to develop new strategies for early diagnosis of GC.

关键词： Biomarkers Gastric cancer Early diagnosis Genetic and epigenetic alterations Circulating molecules

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Novel approaches in search for biomarkers of cholangiocarcinoma

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World Journal of Gastroenterology 2022年第15期28卷 1508-1525页

作者： Lavinia-Patricia Mocan Maria Ilieș carmen Stanca Melincovici Mihaela Spârchez RareșCrăciun Iuliana Nenu Adelina Horhat Cristian Tefas Zeno Spârchez cristina Adela Iuga Tudor Mocan carmen Mihaela Mihu Department of Histology Faculty of Medicine"Iuliu Hațieganu"University of Medicine and PharmacyCluj-Napoca 400012Romania Department of Proteomics and Metabolomics MedFUTURE Research Center for Advanced Medicine"Iuliu Hațieganu"University of Medicine and PharmacyCluj-Napoca 400349Romania ^(nd)Pediatrics Department Faculty of Medicine"Iuliu Hațieganu"University of Medicine and PharmacyCluj-Napoca 400012Romania ^(rd)Medical Department Faculty of Medicine"Iuliu Hațieganu"University of Medicine and PharmacyCluj-Napoca 400012Romania Department of Gastroenterology "Prof.dr.Octavian Fodor"Institute for Gastroenterology and HepatologyCluj-Napoca 400162Romania Department of Pharmaceutical Analysis Faculty of Pharmacy"Iuliu Hațieganu"University of Medicine and PharmacyCluj-Napoca 400012Romania

Cholangiocarcinoma(CCA)arises from the ductular epithelium of the biliary tree,either within the liver(intrahepatic CCA)or more commonly from the extrahepatic bile ducts(extrahepatic CCA).This disease has a poor prognosis and a growing worldwide prevalence.The poor outcomes of CCA are partially explained by the fact that a final diagnosis is challenging,especially the differential diagnosis between hepatocellular carcinoma and intrahepatic CCA,or distal CCA and pancreatic head adenocarcinoma.Most patients present with an advanced disease,unresectable disease,and there is a lack in non-surgical therapeutic modalities.Not least,there is an acute lack of prognostic biomarkers which further complicates disease management.Therefore,there is a dire need to find alternative diagnostic and follow-up pathways that can lead to an accurate result,either singlehandedly or combined with other methods.In the"-omics"era,this goal can be attained by various means,as it has been successfully demonstrated in other primary tumors.Numerous variants can reach a biomarker status ranging from circulating nucleic acids to proteins,metabolites,extracellular vesicles,and ultimately circulating tumor cells.However,given the relatively heterogeneous data,extracting clinical meaning from the inconsequential noise might become a tall task.The current review aims to navigate the nascent waters of the non-invasive approach to CCA and provide an evidence-based input to aid clinical decisions and provide grounds for future research.

关键词： Cholangiocarcinoma Biomarker Proteomics Metabolomics Extracellular vesicles Circulating nucleic acids

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New therapeutic options opened by the molecular classification of gastric cancer

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World Journal of Gastroenterology 2018年第18期24卷 1942-1961页

作者： Mihaela Chivu-Economescu Lilia Matei Laura G Necula Denisa L Dragu Coralia Bleotu carmen C diaconu Department of Cellular and Molecular Pathology Stefan S. Nicolau Institute of Virology Nicolae Cajal Institute Titu Maiorescu University

Gastric cancer(GC) is one of the most lethal and aggressive cancers, being the third cause of cancer related death worldwide. Even with radical gastrectomy and the latest generation of molecular chemotherapeutics, the numbers of recurrence and mortality remains high. This is due to its biological heterogeneity based on the interaction between multiple factors, from genomic to environmental factors, diet or infections with various pathogens. Therefore, understanding the molecular characteristics at a genomic level is critical to develop new treatment strategies. Recent advances in GC molecular classification provide the unique opportunity to improve GC therapy by exploiting the biomarkers and developing novel targeted therapy specific to each subtype. This article highlights the molecular characteristics of each subtype of gastric cancer that could be considered in shaping a therapeutic decision, and also presents the completed and ongoing clinical trials addressed to those targets. The implementation of the novel molecular classification system will allow a preliminary patient selection for clinical trials, a mandatory issue if it is desired to test the efficacy of a certain inhibitor to the given target. This will represent a substantial advance as well as a powerful tool for targeted therapy. Nevertheless, translating the scientific results into new personalized treatment opportunities is needed in order to improve clinical care, the survival and quality of life of patients with GC.

关键词： Gastric cancer Molecular classification Immunotherapy Targeted therapy Clinical trials

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Characterization of human retinal vessel arborisation in normal and amblyopic eyes using multifractal analysis

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International Journal of Ophthalmology(English edition) 2015年第5期8卷 996-1002页

作者： Stefan Tǎlu cristina Vlǎdutiu carmen A.Lupascu Discipline of Descriptive Geometry and Engineering Graphics Department of Automotive Engineering and TransportationFaculty of Mechanical EngineeringTechnical University of Cluj-Napoca Discipline of Ophthalmology Department of Surgical Specialties and Medical ImagingFaculty of Medicine"Iuliu Hatieganu" University of Medicine and Pharmacy Cluj-Napoca Department of Mathematics and Informatics University of Palermo

AIMTo characterize the human retinal vessel arborisation in normal and amblyopic eyes using multifractal geometry and lacunarity parameters.METHODSMultifractal analysis using a box counting algorithm was carried out for a set of 12 segmented and skeletonized human retinal images, corresponding to both normal (6 images) and amblyopia states of the retina (6 images).RESULTSIt was found that the microvascular geometry of the human retina network represents geometrical multifractals, characterized through subsets of regions having different scaling properties that are not evident in the fractal analysis. Multifractal analysis of the amblyopia images (segmented and skeletonized versions) show a higher average of the generalized dimensions (Dq) for q=0, 1, 2 indicating a higher degree of the tree-dimensional complexity associated with the human retinal microvasculature network whereas images of healthy subjects show a lower value of generalized dimensions indicating normal complexity of biostructure. On the other hand, the lacunarity analysis of the amblyopia images (segmented and skeletonized versions) show a lower average of the lacunarity parameter Λ than the corresponding values for normal images (segmented and skeletonized versions).CONCLUSIONThe multifractal and lacunarity analysis may be used as a non-invasive predictive complementary tool to distinguish amblyopic subjects from healthy subjects and hence this technique could be used for an early diagnosis of patients with amblyopia.

关键词： retina retinal vessels amblyopia strabismus multifractals lacunarity

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Evaluation of oxidative stress levels in obesity and diabetes by the free oxygen radical test and free oxygen radical defence assays and correlations with anthropometric and laboratory parameters

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World Journal of Diabetes 2020年第5期11卷 193-201页

作者： Mihnea-Alexandru Găman Mirela Elena Epîngeac Camelia cristina diaconu Amelia Maria Găman "Carol Davila"University of Medicine and Pharmacy Bucharest 050474Romania Department of Hematology Center of Hematology and Bone Marrow TransplantationFundeni Clinical InstituteBucharest 022328Romania Department of Pathophysiology University of Medicine and Pharmacy of CraiovaCraiova 200349Romania Internal Medicine Clinic Clinical Emergency Hospital of BucharestBucharest 014461Romania Clinic of Hematology Filantropia City HospitalCraiova 200143Romania

BACKGROUND Obesity and diabetes are associated with high levels of oxidative stress.In Romanian patients with obesity and(or)diabetes,this association has not been sufficiently explored.AIM To evaluate oxidative stress in obese and(or)diabetic subjects and to investigate the possible correlations between oxidative stress and anthropometric/biochemical parameters.METHODS Oxidative stress was evaluated from a single drop of capillary blood.Reactive oxygen species(ROS)were evaluated using the free oxygen radical test(FORT).The free oxygen radical defence(FORD)assay was used to measure antioxidant levels.RESULTS FORT levels were higher in obese subjects(3.04±0.36 mmol/L H2O2)vs controls(2.03±0.14 mmol/L H2O2)(P<0.0001).FORD levels were lower in obese subjects(1.27±0.13 mmol/L Trolox)vs controls(1.87±1.20 mmol/L Trolox)(P=0.0072).Obese diabetic subjects had higher FORT values(3.16±0.39 mmol/L H2O2)vs non-diabetic counterparts(2.99±0.33 mmol/L H2O2)(P=0.0233).In obese subjects,FORT values correlated positively with body mass index(BMI)(r=0.48,P=0.0000),waist circumference(WC)(r=0.31,P=0.0018),fasting plasma glucose(FPG)(r=0.31,P=0.0017),total cholesterol(TC)(r=0.27,P=0.0068)and uric acid(r=0.36,P=0.0001).FORD values correlated negatively with BMI(r=-0.43,P=0.00001),WC(r=-0.28,P=0.0049),FPG(r=-0.25,P=0.0130),TC(r=-0.23,P=0.0198)and uric acid(r=-0.35,P=0.0002).In obese diabetic subjects,FORT values correlated positively with BMI(r=0.49,P=0.0034)and TC(r=0.54,P=0.0217).FORD values were negatively associated with BMI(r=-0.54,P=0.0217)and TC(r=-0.58,P=0.0121).CONCLUSION Oxidative stress levels,as measured by the FORT and FORD assays,were higher in obese subjects vs controls.ROS levels were elevated in diabetic obese patients vs obese non-diabetic patients and controls.

关键词： Oxidative stress Obesity Diabetes Reactive oxygen species Antioxidants Dyslipidaemia

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