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The bone marrow niche landscape:a journey through aging,extrinsic and intrinsic stressors in the haemopoietic milieu

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Journal of Cancer Metastasis and Treatment 2022年第1期8卷 526-537页

作者： Antonio Giovanni Solimando Assunta Melaccio Angelo Vacca Roberto Ria Department of Biomedical Sciences and Human Oncology Section of Internal Medicine and Clinical OncologyUniversity of Bari Medical SchoolBari 70124 Italy

Inflammation and its effects in the bone marrow microenvironment represent a paradigmatic condition in which the hematopoietic niche and the immune systems,thought to properly sustain blood cell production and distinguish between friend and foe,can actively sustain a corrupted neighborhood within a chronic aberrant inflamed state.The bone marrow niche hijacks the physiologic hematopoiesis.The interactions between the hematopoietic stem cells and the niche in the bone marrow are critical determinants of quiescence.We examined several approaches to confront the available evidence;three key points emerged,pointing to the chronic inflammation process,especially the chronic infection and systemic inflammatory states,as leading causes of hematopoietic stem cell depletion.Clonal hematopoiesis,defined as a relative expansion of individual clones,is caused by somatic alterations in essential hematopoietic genes,which increase stem cell fitness.Moreover,terminal differentiation plays a significant role in progenitor loss and inflammatory signaling,promoting clonal selection and clonal hematopoiesis conditions.Specific myeloid malignancies as paradigmatic examples are discussed as a condition associated with inflammation,including the 5q-syndrome,Philadelphia negative myeloproliferative neoplasms,and chronic myeloid leukemia.Aging with increased fitness and hematopoietic stem cell attrition,extrinsic stress,enhanced stressor-specific fitness,and intrinsic defect across the hematopoietic process represent the route for novel insights in defective hematopoiesis.The discussion in this review also points out that the hematopoietic niches’inflammatory stimulation may affect differentiation patterns and the function of downstream cells.

关键词： Hematopoietic niche immune system inflammation tumor microenvironment

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Leptomeningeal metastases from non-small cell lung cancer:state of the art and recent advances

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 501-520页

作者： Alessia Pellerino Valeria Internò Erminia Muscolino Francesca Mo Francesco Bruno Edoardo Pronello Federica Franchino Riccardo Soffietti Roberta Rudà department of Neuro-oncology University and City of Health and Science HospitalTurin 10126Italy Department of Biomedical Sciences and Human Oncology University of Bari Aldo MoroBari 70121Italy

Patients with leptomeningeal metastases(LM)from non-small cell lung cancer(NSCLC)have a poor outcome with survival of less than 1 year regardless of advancements in treatment strategy.In the past,some randomized clinical trials have been conducted with heterogeneous inclusion criteria,diagnostic parameters,response evaluation and primary endpoints.Efforts to develop a standardized magnetic resonance imaging(MRI)assessment and liquid biopsy techniques to monitor disease evolution in plasma or cerebrospinal fluid(CSF)are underway.This review aims to cover the main clinical and diagnostic challenges of LM from NSCLC,in particular the role of MRI,CSF cytology and liquid biopsy for the diagnosis and monitoring of the disease,as well as the most recent clinical trials on targeted therapies.Targeted therapy,such as epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase rearranged inhibitors,represent a feasible treatment with encouraging results in terms of disease control and survival.For ineligible patients,immune checkpoint inhibitors could represent a therapeutic option with acceptable tolerance,although clinical trials focused on LM from NSCLC are lacking and represent a research focus for the future.

关键词： Anaplastic lymphoma kinase inhibitors epidermal growth factor receptor tyrosine kinase inhibitors clinical trials immunotherapy leptomeningeal metastases liquid biopsy

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Carbon monoxide contributes to the constipating effects of granisetron in rat colon

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World Journal of Gastroenterology 2016年第42期22卷 9333-9345页

作者： Carmela Nacci Margherita Fanelli Maria Assunta Potenza Valentina Leo Monica Montagnani Maria Antonietta De Salvia Department of Biomedical Sciences and Human Oncology - Pharmacology Section Medical School University of Bari "Aldo Moro" department of Interdisciplinary Medicine Medical School University of Bari "Aldo Moro"

AIM To investigate the mechanisms underlying the potential contribution of the heme oxygenase/carbon monoxide(HO/CO) pathway in the constipating effects of granisetron. METHODS For in vivo studies, gastrointestinal motility was evaluated in male rats acutely treated with granisetron [25, 50, 75 μg/kg/subcutaneous(sc)], zinc protoporphyrin IX [Zn PPIX, 50 μg/kg/intraperitoneal(ip)] and hemin(50 μmol/L/kg/ip), alone or in combination. For in vitro studies, the contractile neurogenic response to electrical field stimulation(EFS, 3, 5, 10 Hz, 14 V, 1 ms, pulse trains lasting 10 s), as well as the contractile myogenic response to acetylcholine(ACh, 0.1-100 μmol/L) were evaluated on colon specimens incubated with granisetron(3 μmol/L, 15 min), Zn PPIX(10 μmol/L, 60 min) or CO-releasing molecule-3(CORM-3, 100, 200, 400 μmol/L) alone or in combination. These experiments were performed under co-treatment withor without atropine(3 μmol/L, a muscarinic receptor antagonist) or NG-nitro-L-Arginine(L-NNA, 100 μmol/L, a nitric oxide synthase inhibitor).RESULTS Administration of granisetron(50, 75 μg/kg) in vivo significantly increased the time to first defecation(P = 0.045 vs vehicle-treated rats), clearly suggesting a constipating effect of this drug. Although administration of Zn PPIX or hemin alone had no effect on this gastrointestinal motility parameter, Zn PPIX co-administered with granisetron abolished the granisetron-induced constipation. On the other hand, co-administration of hemin and granisetron did not modify the increased constipation observed under granisetron alone. When administered in vitro, granisetron alone(3 μmol/L) did not significantly modify the colon's contractile response to either EFS or ACh. Incubation with Zn PPIX alone(10 μmol/L) significantly reduced the colon's contractile response to EFS(P = 0.016) but had no effect on contractile response to ACh. Co-administration of Zn PPIX and atropine(3 μmol/L) abolished the Zn PPIX-mediated decrease in contractile response to EFS. Conversely, incubation wit

关键词： Granisetron 碳一氧化物 Heme oxygenase 冒号收缩神经原的反应 Myogenic 反应

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Childhood obesity, cardiovascular and liver health: a growing epidemic with age

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World Journal of Pediatrics 2020年第5期16卷 438-445页

作者： Maria Felicia Faienza Mariangela Chiarito Emilio Molina-Molina Harshitha Shanmugam Frank Lammert Marcin Krawczyk Gabriele D'Amato Piero Portincasa Section of Pediatrics Department of Biomedical Sciences and Human OncologyUniversity of Bari"Aldo Moro"BariItaly Clinica Medica"A.Murri" Department of Biomedical Sciences and Human OncologyUniversity of Bari"Aldo Moro"BariItaly department of MedicineⅡ Saarland University Medical CenterSaarland UniversityHomburgGermany Laboratory of Metabolic Liver Diseases Center for Preclinical ResearchDepartment of GeneralTransplant and Liver SurgeryMedical University of WarsawWarsawPoland Neonatal Intensive Care Unit Di Venere HospitalBariItaly

Background The frequency of childhood obesity has increased over the last 3 decades,and the trend constitutes a worrisome epidemic worldwide.With the raising obesity risk,key aspects to consider are accurate body mass index classification,as well as metabolic and cardiovascular,and hepatic consequences.Data sources The authors performed a systematic literature search in PubMed and EMBASE,using selected key words(obesity,childhood,cardiovascular,liver health).In particular,they focused their search on papers evaluating the impact of obesity on cardiovascular and liver health.Results We evaluated the current literature dealing with the impact of excessive body fat accumulation in childhood and across adulthood,as a predisposing factor to cardiovascular and hepatic alterations.We also evaluated the impact of physical and dietary behaviors starting from childhood on cardio-metabolic consequences.Conclusions The epidemic of obesity and obesity-related comorbidities worldwide raises concerns about the impact of early abnormalities during childhood and adolescence.Two key abnormalities in this context include cardiovascular diseases,and non-alcoholic fatty liver disease.Appropriate metabolic screenings and associated comorbidities should start as early as possible in obese children and adolescents.Nevertheless,improving dietary intake and increasing physical activity performance are to date the best therapeutic tools in children to weaken the onset of obesity,cardiovascular diseases,and diabetes risk during adulthood.

关键词： Cardiovascular Childhood Liver health Obesity

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Dynamic carbon 13 breath tests for the study of liver function and gastric emptying

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Gastroenterology Report 2015年第1期3卷 12-21页

作者： Leonilde Bonfrate Ignazio Grattagliano Giuseppe Palasciano Piero Portincasa Department of Biomedical Sciences and Human Oncology Clinica Medica‘A.Murri’University of Bari Medical SchoolBariItaly Italian College of General Practitioners Florence and BariItaly

In gastroenterological practice,breath tests(BTs)are diagnostic tools used for indirect,non-invasive assessment of several pathophysiological metabolic processes,by monitoring the appearance in breath of a metabolite of a specific substrate.Labelled substrates originally employed radioactive carbon 14(^(14)C)and,more recently,the stable carbon 13 isotope(^(13)C)has been introduced to label specific substrates.The ingested^(13)C-substrate is metabolized,and exhaled^(13)CO_(2)is measured by mass spectrometry or infrared spectroscopy.Some^(13)C-BTs evaluate specific(microsomal,cytosolic,and mitochondrial)hepatic metabolic pathways and can be employed in liver diseases(i.***.simple liver steatosis,non-alcoholic steato-hepatitis,liver fibrosis,cirrhosis,hepatocellular carcinoma,drug and alcohol effects).Another field of clinical application for^(13)C-BTs is the assessment of gastric emptying kinetics in response to liquids(^(13)C-acetate)or solids(^(13)C-octanoic acid in egg yolk or in a pre-packed muffin or the^(13)C-Spirulina platensis given with a meal or a biscuit).Studies have shown that^(13)C-BTs,used for gastric emptying studies,yield results that are comparable to scintigraphy and can be useful in detecting either delayed-(gastroparesis)or accelerated gastric emptying or changes of gastric kinetics due to pharmacological effects.Thus,^(13)C-BTs represent an indirect,cost-effective and easy method of evaluating dynamic liver function and gastric kinetics in health and disease,and several other potential applications are being studied.

关键词： breath tests stable isotope hepatic metabolism gastric motility scintigraphy

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Identify multiple myeloma stem cells: Utopia?

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World Journal of Stem Cells 2015年第1期7卷 84-95页

作者： Ilaria Saltarella Aurelia Lamanuzzi Antonia Reale Angelo Vacca Roberto Ria Department of Biomedical Sciences and Human Oncology Section of Internal Medicine "G. Baccelli" University of Bari "Aldo Moro" Medical School Policlinico I-70124 Bari Italy

Multiple myeloma(MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells(CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activate stemness signaling(Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.

关键词： Bone marrow microenvironment Cancerstem cells Multiple myeloma Stem cells niche Stemness

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肠易激综合征与饮食干预

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Gastroenterology Report 2017年第1期5卷 11-19,I0001页

作者： Piero Portincasa Leonilde Bonfrate Ornella de Bari Anthony Lembo Sarah Ballou Clinica Medica A.Murri Department of Biomedical Sciences and Human OncologyUniversity of Bari Aldo Moro Medical SchoolBariItaly department of Medicine and Gastroenterology Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA

肠易激综合征(IBS)系胃肠道慢性功能性疾病,是最常见的胃肠疾病之一。由于IBS患病率高、治疗效果欠佳、经济负担显著,其对一般人群的影响甚大。IBS的病理生理十分复杂,其治疗主要是对症治疗。对于IBS最常采用的治疗方式包括教育和安抚... 详细信息

肠易激综合征(IBS)系胃肠道慢性功能性疾病,是最常见的胃肠疾病之一。由于IBS患病率高、治疗效果欠佳、经济负担显著,其对一般人群的影响甚大。IBS的病理生理十分复杂,其治疗主要是对症治疗。对于IBS最常采用的治疗方式包括教育和安抚、生活方式的调整(尤其是营养干预)、外周药物(一般是针对肠道动力)、中枢药物(针对内脏高敏性和疼痛)及心理干预(旨在减少应激和症状引起的焦虑)。有效的饮食调节可能包括以下措施:低FODMAPs(发酵的低聚糖、单糖、二糖及多元醇)饮食,限制或禁食产气食物和/或乳糖和麸类食物,补充纤维素。一些新的治疗药物,如某些保健品,也可以作为IBS患者的一项治疗选择。本文重点探讨IBS的饮食干预,对基于营养的饮食治疗的循证医学证据进行了综述。

关键词：肠易激综合征功能性胃肠疾病 FODMAPs 耐受性肠道微生态

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Renal cell carcinoma and viral infections:A dangerous relationship?

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World Journal of Nephrology 2022年第1期11卷 1-12页

作者： Melissa Bersanelli Chiara Casartelli Sebastiano Buti Camillo Porta Medical oncology Unit University Hospital of ParmaParma 43126Italy department of Medicine and Surgery University of ParmaParma 43126Italy Department of Biomedical Sciences and Human Oncology University of Bari‘A.Moro’Bari 70121Italy department of Medical oncology Policlinico ConsorzialeBari 70124Italy

Virus-related cancers in humans are widely recognized,but in the case of renal cancer,the link with the world of viruses is not clearly established in humans,despite being known in animal biology.In the present review,we aimed to explore the literature on renal cell carcinoma(RCC)for a possible role of viruses in human RCC tumorigenesis and immune homeostasis,hypothesizing the contribution of viruses to the immunogenicity of this tumor.A scientific literature search was conducted using the PubMed,Web of Science,and Google Scholar databases with the keywords“virus”or“viruses”or“viral infection”matched with(“AND”)“renal cell carcinoma”or“kidney cancer”or“renal cancer”or“renal carcinoma”or“renal tumor”or“RCC”.The retrieved findings evidenced two main aspects testifying to the relationship between RCC and viruses:The presence of viruses within the tumor,especially in non-clear cell RCC cases,and RCC occurrence in cases with pre-existing chronic viral infections.Some retrieved translational and clinical data suggest the possible contribution of viruses,particularly Epstein-Barr virus,to the marked immunogenicity of sarcomatoid RCC.In addition,it was revealed the possible role of endogenous retrovirus reactivation in RCC oncogenesis,introducing new fascinating hypotheses about this tumor’s immunogenicity and likeliness of response to immune checkpoint inhibitors.

关键词： Renal cell carcinoma Renal cancer Kidney cancer Viruses Viral infections Retrotransposons

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Ferroptosis as an important driver of lupus

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Protein & Cell 2022年第5期13卷 313-315页

作者： Chao Mao Guang Lei Li Zhuang Boyi Gan department of Experimental Radiation oncology The University of Texas MD Anderson Cancer CenterHoustonTXUSA The University of Texas MD Anderson UTHealth Graduate School of biomedical sciences HoustonTXUSA

Systemic lupus erythematosus(SLE),the most common form of lupus,is a chronic autoimmune disorder characterized by a global loss of self-tolerance and hyper-activation of both innate and adaptive immune systems(Kaul et al.,2016).Neutrophils,the most abundant leukocytes in human blood,have a critical role in maintaining immune surveillance and tissue homeostasis,and its dysregulation is of high relevance to SLE(Ricklin et al.,2010).In patients with SLE,accelerated neutrophil death and the deficiency in clearing dying neutrophils cause nuclear and cytoplasmic antigen exposure,excessive production of type I interferon(IFN),and neutrophil extracellular trap(NET)release,subsequently inducing autoimmune responses(Garcia-Romo et al.,2011).Dysregulated neutrophil death is believed to be a major cause of SLE;however,the underlying mechanism of neutrophil death in SLE is not well-defined.

关键词： al. lupus autoimmune

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Recent advances in the frontline treatment of metastatic renal cell carcinoma

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Journal of Cancer Metastasis and Treatment 2021年第1期7卷 695-706页

作者： Camillo Porta Mimma Rizzo Department of Biomedical Sciences and Human Oncology University of Bari‘A.Moro’Bari 70124Italy Division of Medical oncology A.O.U.Consorziale Policlinico di BariBari 70124Italy Division of Translational oncology I.R.C.C.S.Istituti Clinici Scientifici MaugeriPavia 27100Italy

We aim to describe the most recent advances in the upfront treatment of metastatic renal cell carcinoma,and to provide criteria-though often subjective-which could be used for treatment selection,by means of a critical review of the results of novel trials of immune-based combinations,coupled with personal considerations and experiences.To date,5 immune-based combinations have been tested within large phase III trials;four of them yielded a significant overall survival benefit(Ipilimumab+Nivolumab,Pembrolizumab+Axitinib,Nivolumab+Cabozantinib and Pembrolizumab+Lenvatinib),while the combination of Avelumab+Axitinib,although reaching study primary endpoint,determined just a significant progression-free survival benefit.In terms of safety,the excess of adverse events is overall counterbalanced to the higher activity of the combinations.Overall,all the discussed immune-based combinations were ultimately approved by different regulatory authorities,and are indeed included in the most important international guidelines.Waiting for longer follow-ups and more mature trial data,as well as for real-world experiences,in the absence of validated biomarkers,our 1st line treatment choice cannot but rely on methodologically incorrect treatment comparisons,personal preferences,and experience.

关键词： Renal cell carcinoma immune checkpoint inhibitors antiangiogenics survival

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