Translational Medicine Reports is a peer-reviewed international journal publishing articles in the field of molecular biology, biochemistry and nanotechnology applied to the treatment of chronic-degenerative diseases including diabetes, cancer, neurological, cardiovascular and metabolic disorders. The aim of the Journal is to contribute to bridging the gap between basic research and clinical applications from an interdisciplinary perspective. Translational Medicine Reports addresses researchers and managers in academia, biotechnology and pharmaceutical industry researchers, physician scientists, etc. Original Articles with interdisciplinary topics, Reviews, Editorials, From Bench-to-Bedside Articles, Conference Proceedings, and Letters to the Editor are welcome. Every article published in the Journal will be peer-reviewed by experts in the field and selected by members of the Editorial Board. The journal is completely free: no charge for publication, as it is supported by private funds.
PAGEPress Scientific Publications, Pavia, Italy
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Ingestion of minoxidil associated with elevated transaminases in the absence of ischemic hepatitis
Minoxidil is a direct-acting vasodilator that induces relaxation of the vascular endothelium, and historically, it has been used as an antihypertensive agent. It caused hypertrichosis, resulting in its typical use today as an alopecia treatment. Toxicity is characterized by hypotension and tachycardia, often requiring treatment with α-adrenergic agonists. A previously healthy 18-year-old woman presented to the emergency department three hours after ingesting 60 mL of 5% W/V topical minoxidil solution. Initial vitals included sinus tachycardia at 117 beats per minute and a blood pressure of 92/44 mmHg. Laboratory analyses performed three hours post-ingestion revealed elevated aspartate and alanine aminotransferases (224 and 384 IU/L, respectively). Acetaminophen and ethanol concentrations were undetectable. Isotonic crystalloid, N-acetylcysteine, phenylephrine, and midodrine were administered. She developed pulmonary edema, requiring diuresis and supplemental oxygen via a nasal cannula. She was discharged 108 hours post-ingestion after a full recovery. Minoxidil toxicity may be an uncommon etiology of abnormal transaminase concentrations.
Copyright (c) 2023 Elizabeth Shanahan, Christopher Mitchell, Richard Chen, Steven Walsh http://creativecommons.org/licenses/by-nc/4.0
Lymphoepithelial carcinoma of the larynx: An unusual response to EXTREME regimen therapy. A new option for treatment?
Lymphoepithelial Carcinoma (LEC), an aggressive variant of Squamous Cell Carcinoma (SCC), is an undifferentiated carcinoma with an intermixed reactive lymphoplasmacytic infiltrate. Most cases of LEC occur in the nasopharynx, while it rarely involves other sites. LEC of larynx and hypopharynx is an extremely rare and aggressive neoplasm, characterized by a high propensity to loco-regional dissemination and a poor prognosis; it represents the 0,2% of all tumours of the larynx. Since it is such a rare tumor, the current literature provides only recommendations and there are no treatment guidelines available. A 70-year-old man with laryngeal LEC and both distant and nodal metastases was treated with chemotherapy, following EXTREME regimen therapy. It was classified as a cT3 N3b M1 glottic cancer (Stage IVC, AJCC 8th Ed.), stage IVC. As the response on metastases was unexpectedly encouraging, surgical treatment on T could be performed. Patient underwent to total laryngectomy and bilateral neck dissection. To date, eight months after surgery, the patient is disease free. The unusual clinical course is reported.
A clinical case of late diagnosis of PAP with good response to whole lung lavage
Pulmonary Alveolar Proteinosis (PAP) is a rare syndrome characterized by the accumulation of surfactant in alveoli and terminal airways resulting in respiratory failure. PAP comprises part of a spectrum of disorders of surfactant homeostasis (clearance and production). We describe the case of a 54 years-old woman hospitalized in March 2017 with diagnosis of acute hypoxemic respiratory failure secondary to pulmonary interstitial disease. In our case, the patient arrived at our observation after developing a severe respiratory insufficiency although a long term history of respiratory symptoms. This diagnostic delay suggests that alveolar proteinosis should always be considered as a possible diagnosis in patients with dyspnea, cough and crazy paving at HRTC. In spite of this the disease resolved with a cycle of total lung lavage and the symptomatology has improved with the resolution of the radiological picture without any other therapeutic approach.
Hemoptysis in a patient with pulmonary angiosarcoma
Pulmonary Artery Angiosarcoma (PAS) is a rare malignant vascular tumor with an aggressive clinical course and poor prognosis. The first line therapy is the surgical resection, but an early diagnosis is difficult due to the nonspecific clinical and radiological manifestations. The purpose of this case report is to analyze the difficulties in PAS diagnosis. A 32 years-old man, with a history of hemoptysis in the last two months, undergoes total body CT, which revealed multiple nodules in his left lung, surrounded by areas of ground glass opacity, without any extra-lung lesion. Fiberoptic bronchoscopy and bronchial washing were negative for neoplastic cells and open lung biopsy was necessary for diagnosis of PAS. A surgical resection was not allowed because the left lung was hepatized, so the surgeon couldn’t reach the hilum; furthermore, the subclavian vessels were infiltrated by cancer. After a month of supportive therapy, the patient died as a consequence of multiple organ failure. Our case report underlines that PAS should be considered as a possible diagnosis for patients with hemoptysis and lung nodules surrounded by ground glass opacity.
An atypical manifestation of lymph node tuberculosis
Tuberculosis is a chronic granulomatous infection caused by Mycobacterium tuberculosis. Since the 80’s, new cases have been increasing especially in developed countries because of spreading of HIVinfection, immunodeficiency and immigration phenomenon. Cervical lymphadenitis is the most frequent localization of extrapulmonary tuberculosis. Clinical manifestations consist in a slow growth and painless swelling of a single or multiple neck nodes, generally unilateral, with rare manifestations of fistulization and of systemic symptoms. Diagnosis is performed by fine-needle aspiration cytology (FNAC) or excisional biopsy integrated by Ziehl-Neelsen stain and Mycobacteria culture. A 57-year-old male patient affected by a right-side large laterocervical swelling. The patient referred that almost one month before he noted the onset of the lesion sizing about 1 cm, so he treated it with antibiotic association of amoxicillin and clavulanate acid without any improvement. The lesion quickly doubled its size, became painful and hyperemic the skin above it. Because of the clinical worsening, the patient undergone to neck ultrasonography that showed a neck mass sizing about 50×25 mm. He began a new antibiotic therapy with Ceftriaxone intra muscle, with no modifications of the lesion. Few days later his clinical conditions drastically got worse - increasing pain and skin fistulization. So he practiced a magnetic resonance imaging of the neck that showed a massive suppurated lesion of the neck. The patient was hospitalized in our Otolaryngology Unit where he began a diagnostic iter in order to clarify the nature of the lesion and differentiate between neoplastic/lymphoproliferative lesion and an infective one. After a biopsy of the lesion, the hysthopatologic examination reported the presence of dense mononuclear cell infiltrate surrounding a set of Langerhans cells, so our diagnostic suspect was addressed to extrapulmonary tuberculosis. The authors report a case of a healthy man without risk factors for tuberculosis infection, come to our attention with a large and aggressive unilateral tubercular cervical lymphadenitis, skin fistulization and no systemic symptoms. To make diagnosis of tubercular lymphadenitis, we sustain that biopsy is still the gold standard if FNAC is in doubt.
Copyright (c) 2019 The Author(s) http://creativecommons.org/licenses/by-nc/4.0
Evaluation of hepatitis B viremia and corresponding antibodies among infected patients attending Abuja Teaching Hospital, Nigeria
In most under-developed and developing countries, diagnosis and treatment of hepatitis B relied mainly on detection of hepatitis B virus (HBV) serological biomarkers. The reliability of these markers in comparison with HBV DNA viral load is required to review their diagnostic value. Thus, this study investigated the serological and HBV viral load profile of persons with hepatitis B attending the University of Abuja Teaching Hospital, Gwagwalada, Nigeria. Attributes of hepatitis B-infected participants (February-May, 2018) were assessed. They included hepatitis B antigens (HBsAg, HBeAg), antibodies (HBsAb, HBcAb, HBeAb) and HBV DNA, using rapid immunichromatigraphical and real-time polymerase chain reaction (qPCR), respectively. Structured questionnaires were used to collate participants biodata. Out of 53 participants, 30 were male and 23 were female. 90.6% (48/53) were positive for HBsAg, 28.3% (15/53) were positive for HBsAb, 60.4% (32/53) were positive for HBcAb, 17.0% (9/53) were positive for HBeAg, while HBeAb was detected in 58.5% (31/53). HBV DNA was significantly associated with HBcAb (χ2=28.622, P=0.000), HBeAg (χ2=11.820, P=0.008), and HBeAb (χ2=16.440, P=0.001). The on-site point of care serological test has significant impact in diagnosis and monitoring Hepatitis B when compared to qPCR.
Chikungunya virus: Update on molecular biology, epidemiology and current strategies
Chikungunya virus (CHIKV), an arthropod-borne virus, is the aetiological agent of a disease characterized by several aspecific symptoms including fever, myalgia and arthralgia. The virus is primarily transmitted to humans through the bite of an infected mosquito of Aedes genus. This virus was first isolated in Tanzania in 1953, from which it spread to other African countries, Asia, Northern and Southern America, Europe and Oceania. Today, many human cases of CHIKV infection have been identified. The diffusion of CHIKV across the world, including Italy, is due to multiple factors amongst which the wide distribution of its vectors and high transmission efficiency play a crucial role. Currently, there are no specific treatments and effective vaccines against CHIKV; indeed, available therapies allow symptoms mitigation and some promising vaccines are undergoing clinical trials. The purpose of this review is to offer an updated picture of CHIKV molecular biology, epidemiology and vector distribution, clinical features and strategies for infection prevention and treatment.
Copyright (c) 2019 Debora Stelitano, Annalisa Chianese, Roberta Astorri, Enrica Serretiello, Carla Zannella, Veronica Folliero, Marilena Galdiero, Gianluigi Franci, Valeria Crudele, Mariateresa Vitiello
West Nile virus: an overview of current information
West Nile Virus (WNV) is a vector-borne flavivirus primarily infecting mosquitoes, birds, horses and humans. WNV is responsible for asymptomatic infections or a variety of clinical manifestations ranging from mild febrile illness to neuroinvasive disease. The frequency and severity of WNV-related disease have lately increased in the European Union and in the neighbouring countries, with particular concern for the Mediterranean area. This trend is probably connected to a raise in both average temperatures and rainfall, favourable factors for WNV spread. Due to the marked and expanding geographical distribution of the vector and the high endemic potential of WNV, this virus is worldwide considered an increasing public health apprehension. An augmented burden of WNV severe illness has been reported. Alarmingly, no vaccine or specific antiviral treatments are currently available for WNV infection. Hereafter, we will review the available information summarizing molecular biology, pathogenesis, clinical manifestations, epidemiology, diagnosis and therapy for WNV infection in humans.
Copyright (c) 2019 Annalisa Chianese, Debora Stelitano, Roberta Astorri, Enrica Serretiello, Maria Teresa Della Rocca, Colombina Melardo, Mariateresa Vitiello, Marilena Galdiero, Gianluigi Franci
Antibacterial and antiviral potential of neuropeptides
The emergence of multidrug resistant bacteria is a global health threat and the discovery of new antimicrobial agents is an absolute priority. In this context endogenous peptides are emerging as novel potential candidates. In this work, we assessed the antimicrobial effects of orexins and ghrelin neuropeptides against gram-negative (Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae) and gram-positive (Staphylococcus aureus) bacteria. Orexin-B and ghrelin showed a potent bactericidal effect at concentration equal to or greater than 25 μg/ml. No antimicrobial activity has been observed for orexin-A. Furthermore, we investigated the antiviral proprieties of the three peptides against herpes simplex virus 1 (HSV-1). We found that orexin-B, but not orexin-A is effective for HSV-1 infectivity inhibition.
Copyright (c) 2019 Carla Zannella, Debora Stelitano, Veronica Folliero, Luciana Palomba, Tiziana Francesca Bovier, Roberta Astorri, Annalisa Chianese, Marcellino Monda, Marilena Galdiero, Gianluigi Franci
Airborne microbial flora in buffalo farms in a Mediterranean climate
The last few decades have seen an increase in intensive buffalo farms worldwide. Such industrialized activity entails human and animal potential health-related hazards as well as for the environment. Given the breadth of the issue, in this study we focused on gathering microbiological air sampling in the Southern Italian buffalo farms in order to obtain further information on airborne microbial flora. In details, we evaluated the bio-aerosol concentration of cultivable bacteria and fungi in ten different buffalo farms. There are evidences showing that exposure to organic dust may exacerbate asthma, just as it may cause mucous membrane irritation and chronic bronchitis. Likewise, studies show that inhaling noninfectious microorganisms and their components may cause inflammation of the respiratory tract. As a result, this is a significant health hazard to these farms’ workers as well as to rural residents living closely to them.
Copyright (c) 2019 Debora Stelitano, Giuseppe Squillaci, Biagio Santella, Annalisa Chianese, Virginia D'Oriano, Emiliana Finamore, Mariateresa Vitiello, Federica Maria Di Lella, Marilena Galdiero, Gianluigi Franci
Relationship between type 2 diabetes and pancreatic cancer
Diabetes mellitus and cancer are conditions that constitute a serious problem for the health of the world’s population, and their co-existence in the same person is becoming increasingly common. Glucose metabolism and the presence of insulin in inflammatory situations appear to be the main factors driving this association, where hyperinsulinemia has been shown to contribute to an increase in risk of association between type 2 diabetes and cancer. Therefore, administering lower levels of exogenously administered insulin to patients with type 1 diabetes would decrease their risk of developing cancer when compared to patients with type 2 diabetes. The results from animal experiments seem promising in terms of pharmacological treatment.
Copyright (c) 2018 M. Temel Yilmaz, Ali Osman Gürol http://creativecommons.org/licenses/by-nc/4.0
New molecular targets for the treatment of neovascular age-related macular degeneration
Age-related macular degeneration (AMD) is a progressive chronic disease that currently represents the leading cause of irreversible vision loss in the western world. Experimental and clinical evidence has demonstrated that vascular endothelial growth factor A (VEGF-A) plays an important role in promoting the choroidal neovascularization that characterizes the wet form of AMD. Intravitreal injection of anti- VEGF-A agents is the current treatment of choice for neovascular AMD (nAMD). These agents have brought about dramatic changes in the treatment of nAMD, but most patients require frequently repeated injections and regular long-term follow-up, with a significant percentage of them showing resistance to anti-VEGF-A drugs. Thus, the identification of additional therapies that could improve the treatment protocols is needed. There are numerous areas of investigation into new treatments, with increasing efforts being made to study drugs that address various targets along the angiogenic signaling cascade, or other pathways related to the onset of nAMD. The aim of the present review is to summarize and discuss promising new therapies and targets that have the potential to improve outcomes and to lengthen treatment durability, especially in patients with recalcitrant or recurrent forms of nAMD.
Copyright (c) 2017 Gian Marco Tosi, Marcella Barbarino, Maurizio Orlandini, Federico Galvagni
Translational research for hepatocellular carcinoma: What’s new?
Hepatocellular carcinoma (HCC) is a heterogeneous disease that usually develops within liver cirrhosis. Cancerogenesis in HCC is not a clear process and, at present, there is not a well-defined sequence of DNA mutations able to explain the entire process, from normal hepatocyte to HCC. Lately, the impact of some oncogenes on HCC development has been studied and some of these genes belong to the MAPKinases pathway, highlighting the importance of downstream effectors stimulated by the interaction between extracellular growth factors and tyrosine kinase receptors. Unfortunately, drugs able to interfere with the aforementioned pathway showed no positive results in clinical trials. A number of preclinical studies have focused the attention on epigenetic changes in HCC cells, focusing on the extensive DNA hypermetilation as a factor causing the knockout of several tumor suppressor genes. Cancerogenesis of HCC, at least at an early phase, could be sustained by epigenetic changes. Finally, some authors have tried to classify HCC on the basis of gene mutations found after performing an extensive genome sequencing, and interestingly, they have identified different classes of HCC on the basis of different clusters of mutated genes. HCC is not characterized by a unique driver mutation, as the case of EGFR mutations for lung cancer or K-Ras mutations for colorectal cancer, thus it is, at present, very difficult to identify a reliable target for antitumoral therapy. This review focuses on current translational research and molecular targets in the treatment of HCC.
Copyright (c) 2017 Salvatore Pisconti, Antonio Gnoni, Giuseppina Della Vittoria Scarpati, Antonella Licchetta, Nicola Silvestris, Mario Giuliano, Michele Montrone, Raffaele Addeo, Francesco Perri, Antonio Giordano
Application of omic technologies in cancer research
Understanding the biology of health and diseases such as cancer, generating insight into the triggers and potentiators of disease and the development of therapeutic approaches to counter and treat disease requires detailed interrogation of inherited genes, and the dynamic positioning of the transcriptome and proteome. In the last 10 years, significant technological developments and increases in sample throughput capabilities have led to a dramatic increase in the size and complexity of the datasets that can be generated. A key challenge now is to develop robust approaches for analysing and interpreting these, and converting data into biologically- and clinically-relevant information. Herein, we provide an overview of approaches for acquiring, integrating and interpreting complex datasets generated using multiple omic platforms, with a focus on the field of cancer research, and highlight key successful data handling and integration applications.
Copyright (c) 2018 Sarah Wagner, Graham R. Ball, A. Graham Pockley, Amanda K. Miles http://creativecommons.org/licenses/by-nc/4.0
Anaplastic lymphoma tyrosine kinase oncogene in human cancer: gene aberrations, methods of detection and therapeutic potential
Anaplastic lymphoma tyrosine kinase (ALK) gene could be an attractive oncotarget in human cancers, since it is involved in several genetic alterations resulting in an aberrant activity of the receptor. To date, ALK-rearrangement represents a molecular target for the treatment of ALK-rearranged Non Small Cell Lung Cancer patients, who are highly sensitive to crizotinib, a specific inhibitor. ALK-rearranged patients treated with crizotinib show relevant clinical implications, however several different resistance mechanisms have been identified. Here we review various critical issues related to ALK-targeting therapy, including ALK gene aberrations, methods of detection, mechanism of acquired resistance and second-generation ALK inhibitors.
Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation
Glucose-6-phosphate dehydrogenase (G6PD) is an oncoprotein that is regulated by the p53 tumor suppressor. Mutant p53 loses the ability to inhibit G6PD, and loss of G6PD control clearly plays a role in oncogenesis. The steroid hormone precursor dehydroepiandrosterone (DHEA) is an endogenous uncompetitive inhibitor of G6PD. In humans, and a few other species, the sulfated circulatory form of DHEA (DHEAS) is present at extremely high concentrations – much higher than can be accounted for by DHEA’s function as a precursor to steroid hormones. Uncompetitive inhibition is extremely rare in natural systems because it is irreversible in the presence of high concentrations of substrate and inhibitor. What has gone unappreciated is that such uncompetitive inhibition can quickly lead to cell death when the target is an obligatory housekeeping gene such as G6PD. Cells with inactivated p53 not only lose control over G6PD, but also over hexokinase (HK), the enzyme that converts glucose into glucose-6-phosphate (G6P), the substrate of G6PD. Furthermore, loss of p53 function de-represses NFκB activity, resulting in the upregulation of steroid sulfatase (SS) which converts circulating DHEAS into active DHEA. We propose that inactivation of p53 rapidly elevates G6P and DHEA concentrations in affected cells, driving uncompetitive inhibition of G6PD to lethal irreversibility. In animals with circulating DHEAS, this kill-switch mechanism may prevent most cases of p53 inactivation from becoming tumorigenic. Tumors would thus represent instances in which this mechanism had not been triggered, but which might still be triggered by application of DHEA sufficient to uncompetitively inhibit tumor G6PD. To test this hypothesis, we performed a pilot study in which dogs with cardiac hemangiosarcoma were treated with high dose (HD) DHEA supplemented with isoprene precursors to maintain geranylation of Rac GTPase. Tumor regression and longevity observed in these dogs supported the concept that some tumors retain extraordinary sensitivity to uncompetitive inhibition by DHEA.
AICC Meeting: The future of cancer therapy: the genome editing era | Catanzaro, Italy, 8-9 June 2017
This issue contains the abstracts presented at AICC Meeting "The future of cancer therapy: the genome editing era" | Catanzaro, Italy, 8-9 June 2017.
Copyright (c) 2017 Maria Teresa Di Martino http://creativecommons.org/licenses/by-nc/4.0
Polycaprolactone nanofiber mesh with adhered liposomes as a simple delivery system for bioactive growth factors
Polycaprolactone (PCL) nanofibers were prepared using electrospinning and functionalized with liposomes containing growth factors by simple surface adhesion. A tight interaction between the liposomes and PCL nanofibers has been clearly demonstrated. Additionally, the interaction of the liposomes with the PCL nanofibers was visualized by FESEM. The potential of the liposome-immobilized scaffold as a delivery system for synthetic growth factors, and as a suitable system for mesenchymal stem cells (MSCs) adhesion and proliferation, was evaluated by confocal microscopy, DNA synthesis rate and dsDNA amount determination. The results showed that the growth factors adhered to the surface of the PCL nanofibers stimulated cell proliferation mainly up to day 7, and that afterwards their effect was significantly lower. By contrast, the release of growth factors from liposomes resulted in gradual proliferation of MSCs throughout the whole experiment. Moreover, the functionalized nanofibers stimulated type II collagen production, which was confirmed by immunohistochemical staining using monoclonal antibody against type II collagen. The study has indicated that growth factor-enriched liposomes adhered to the PCL nanofiber system could be useful as a drug delivery tool in various biomedical applications.
Copyright (c) 2018 Andrea Mickova, Karolina Vocetkova, Vera Sovkova, Mikala Rampichova, Matej Buzgo, Eva Filova, Evzen Amler
Stealth liposomes for the delivery of zoledronic acid into tumors enhance the anticancer activity of the drug
Zoledronic acid (ZOL) is a third generation aminobisphosphonate, commonly used for the treatment of bone metastases. Several studies have shown a direct in vitro antitumor activity of ZOL but a clear evidence of clinical activity is still lacking. Unfortunately, the use of ZOL as an anticancer agent in extraskeletal tissues is limited probably because it is rapidly removed from the blood and tends to accumulate in the bone. On these bases, we developed stealth liposomes encapsulating ZOL (Lipo- ZOL) to improve the pharmacokinetic profile of the drug. Compared to free ZOL, Lipo-ZOL induced a stronger inhibition of growth in two different cancer cell lines H460 and CG5. Moreover, Lipo-ZOL also significantly caused a larger inhibition of tumor growth and increased the overall survival in murine models of human lung and breast cancer, in comparison with free ZOL. These results suggest the use of Lipo-ZOL as a potential anticancer agent in patients with neoplastic disease.
Copyright (c) 2017 Silvia Zappavigna, Amalia Luce, Manuela Porru, Alessia Maria Cossu, Carmela Ferri, Sara Lusa, Marianna Abate, Giuseppe De Rosa, Michele Caraglia, Carlo Leonetti http://creativecommons.org/licenses/by-nc/4.0
Efficacy of ChemoID® guided drug selection for palliative chemotherapy in advanced recurrent high-grade ovarian adenocarcinoma: Case study
Notwithstanding tremendous advances in surgery, primary chemotherapy, and novel treatments for recurrent disease, the diagnosis of advanced epithelial ovarian cancer (EOC) in 2016 remains ultimately fatal in the majority of cases. Advanced therapy refractory EOC patients are often treated in hospice and with chemotherapy palliative care. The main goals of chemotherapy for recurrent/refractory ovarian cancer are the palliation of disease-related symptoms, and improvement of quality and quantity of life. Unfortunately, there is contradicting evidence suggesting that chemotherapy has a role in palliation of symptoms with an apparent improvement in quality of life. Anticancer drugs have a high rate of failure and chemotherapy response assays have been used to identify which drugs are more likely to be effective against those of gynecological origin. ChemoID® is a functional drug response assay which measures the sensitivity of cancer stem cells (CSCs) and bulk of tumor cells to chemotherapy to determine the most effective combination of anticancer drugs for solid tumors. We present a clinical case that demonstrates the utility of ChemoID® guidance to commonly available drugs with identified toxicity profiles and predictable cost profile available at POS, along with rapid response in correcting symptomatic disease features, and minimal treatment burden from toxicities. We observed in the reported case the survival and symptom management benefits of ChemoID® guided therapy even after plateau of response to cisplatin. Further studies are indicated to increase the clinical adoption of ChemoID® for gynecological malignancies in the palliative setting.
Copyright (c) 2017 Timothy DeEulis, Candace M Howard, Jagan Valluri, Pier Paolo Claudio
Genome-wide profiling of congenital insulin-like growth factor-1 deficient patients: translational implications in cancer prevention and metabolism
Laron syndrome (LS) is a rare genetic disorder identified in the 1950s by Professor Zvi Laron. LS results from mutation of the growth hormone receptor (GH-R) gene, leading to congenital insulin-like growth factor-1 (IGF1) deficiency and dwarfism. Recent epidemiological studies have shown that LS patients do not develop cancer, emphasizing the crucial role of the IGF1 axis in cancer biology. Genome-wide profiling of LS patients conducted in our laboratory led to the identification of genes and signaling pathways that are over- or under-represented in LS compared to healthy controls of the same age range and ethnic group. Differentially expressed genes may be responsible for the association between lifetime low IGF1 values and protection from cancer. This experiment of nature may provide invaluable information that might translate into novel therapeutic approaches in modern oncology.
Copyright (c) 2017 http://creativecommons.org/licenses/by-nc/4.0
Possible roles of transglutaminases in molecular mechanisms responsible for cancer and human neurodegenerative diseases
Transglutaminases are a family of Ca2+- dependent enzymes which catalyze posttranslational modifications of proteins. The main activity of these enzymes is the crosslinking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted/ crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for either physiological or pathological processes. In particular, transglutaminase activity has been shown to be responsible for human autoimmune diseases and Celiac Disease is just one of them. Interestingly, cancer and neurodegenerative diseases, such as Alzheimer’s Disease, Parkinson’s Disease, supranuclear palsy and Huntington’s Disease, are characterized in part by aberrant transglutaminase activity and by increased cross-linked proteins in affected tissues. This review describes the possible molecular mechanisms by which these enzymes could be responsible for such diseases and the possible use of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity.
Copyright (c) 2017 Gabriella Misso, Nicola Gaetano Gatta, Mayra Rachele Zarone, Gaetano Cammarota, Anna Grimaldi, Vittorio Gentile http://creativecommons.org/licenses/by-nc/4.0
The role of mouse models in translational cancer research: present and future directions
A major issue in the research for new anticancer therapeutics is represented by the low number of new compounds approved for clinical use in comparison to the good success rate reported in preclinical studies. This high attrition rate could be attributed to many factors including the unsatisfactory predictive value of experiments performed in animals. To this purpose, general opinions suggest that classical models as murine tumors and xenografts do not mimic the complexity of human cancer diseases and that the use and integration of different relevant mouse models could improve the efficiency of the drug development process. In this review, we overview the present state of research in the field of mouse models for cancer and describe the advantages and limitations of the different models. Finally, strategies for improving the predictive value of animal experiments will be also discussed.
Copyright (c) 2017 Carlo Leonetti http://creativecommons.org/licenses/by-nc/4.0
The sense of smell, like taste and trigeminal senses, is a chemical sense dedicated to the perception of chemical stimulations and to the generation of responses to them. Although, from an evolutionary perspective, the chemical senses are the oldest of our senses, our knowledge on the neural processing of the three chemical senses is still incomplete and has been considerably lagging behind that of our other senses. The current review aims to give an overview about human smell function. In particular we focus on the anatomy and physiology of the olfactory system, the epidemiology and the causes of olfactory loss, and on the clinical management of olfactory disorders stressing the impact of smell loss on the quality of life. Lastly, we emphasize the importance of olfaction in every day life. In our opinion, the impairment of sense of smell should be taken into serious consideration by the clinicians, as it could be the indicator of important systemic diseases or the cause of domestic accidents.
Copyright (c) 2017 Teresa Abate, Elena Cantone, Filippo Ricciardiello, Rossella Cuofano, Giovanni Castagna, Flavia Oliva, Giuliano Sequino, romolo villani, Maurizio Iengo http://creativecommons.org/licenses/by-nc/4.0
Gaba-betaine modulates SIRT1 and p16INK4A expression during high-glucose induced endothelial cell senescence
Gaba-betaine (γ-aminobutyric acid betaine, GabaBet), a betaine formed by trimethyllysine (TML), is a precursor of the L-carnitine biosynthesis. Betaine, quaternary ammonium compounds, are naturally occurring osmoprotectants or compatible solutes with a widespread distribution in plant and animal kingdoms. Among betaines, stachydrine (N,N-dimethyl-L-proline) (ProBet), abundant in citrus fruit juices, inhibits the deleterious effect of high-glucose (hGluc) on endothelial cells (EC). Hyperglycaemia induces endothelial dysfunction and vascular complications by promoting EC senescence, altering antioxidant enzyme involved in the system defence against reactive oxygen species (ROS), and limiting the cell proliferative potential. This study was designed to determine the possible effect of GabaBet against the hGluc-induced oxidative injury. Evaluation of cell viability revealed that GabaBet does not affect cell proliferation from 0.001 to 1mM up to 72 h. Of interest, co-treatment for 48 h with GabaBet (0.1 mM) and hGluc (30 mM) (GabaBet+hGluc) attenuated the EC growth arrest in the G0/G1 cell cycle phase. GabaBet counteracted the hGluc induced upregulation of p16INK4A and the increased superoxide dismutase activity. Moreover, the downregulation of sirtuin 1 (SIRT1) expression, occurring under hGluc conditions, is significantly blocked by GabaBet. On the whole, results show that beneficial effects of GabaBet in the prevention of hGluc-induced endothelial senescence is paralleled by the modulation of SIRT1 and p16INK4A expression levels.
Copyright (c) 2017 Nunzia D’Onofrio, Luigi Servillo, Alfonso Giovane, Rosario Casale, Domenico Cautela, Domenico Castaldo, Maria Luisa Balestrieri http://creativecommons.org/licenses/by-nc/4.0
Tissue-specific cancer stem cells: reality or a mirage?
Equo ne credite, Teucri. Quidquid id est, timeo Danaos et dona ferentes (Do not trust the horse, Trojans! Whatever it is, I fear the Greeks, even bringing gifts) said Laocoön (Virgil, the Aeneid book). Cancer stem cells (CSCs) are populations of cancer cells that can be found in different cancerous tissues and organs, and have properties that are similar to normal stem cells. They are thought to be chemo-resistant and radioresistant and are therefore responsible for cancer recurrence and relapse encountered in cancer patients following chemotherapy and radiotherapy. Although significant progress has been made to characterise CSCs, it is becoming clear that the failure of cancer therapies directed against certain types of aggressive cancers is due to the presence of these malignant cells. Cancer therapies that will rely on a combination of CSCs-targeted therapies, chemotherapy and radiotherapy are more likely to succeed in eradicating aggressive cancers and prevent recurrence in treated patients.
Early detection of laryngeal cancer: prominence of miRNA signature as a new tool for clinicians
Early detection of laryngeal cancer, essential in the initial stages of the disease to achieve a high survival rate, is unfortunately hampered by the lack of specific symptoms. In this regard, there is a pressing need to dispose of reliable and non-invasive diagnostic and prognostic markers for a real time monitoring availing of accurate and reproducible methods, in order ensure applicability for early diagnosis and primary and secondary prevention. This review focuses on the recent reports that emphasize the crucial role of miRNAs in regulating laryngeal cancer tumorigenesis. In detail, we have reported the most characterized miRNAs with an established oncogenic or oncosuppressive role in cell biology of laryngeal cancer, also describing, for each of them, the main molecular mechanisms responsible for their specific function. We have also defined the potential of miRNAs as novel diagnostic and prognostic markers in virtue of their differential expression between laryngeal carcinoma tissues and the adjacent normal counterpart. Moreover, their proven stability in systemic circulation and other body fluids, as well as their easy detection and quantization, makes the analysis of miRNA signatures an excellent tool for clinicians as hallmark for cancer classification and diagnosis. Moreover, an eventual similarity between deregulated miRNAs in tumor tissues and in body fluids would allow to provide a considerable advantage for patients’ compliance, replacing invasive tissue biopsies with simple assays on easily obtained blood products.
Copyright (c) 2017 Hiromichi Kawasaki, Mayra Rachele Zarone, Angela Lombardi, Filippo Riccciardiello, Michele Caraglia, Gabriella Misso
Sudden sensorineural hearing loss: role of hyperbaric oxygen therapy
Sudden sensorineural hearing loss is defined as an acute hearing reduction of 30 dB or more, in at least three consecutive frequencies, occurring within 3 days of symptom onset. There is no consensus on the best treatment option. The aims of this paper were to evaluate the effectiveness of a treatment protocol based on medical therapy combined with hyperbaric oxygen therapy and to examine the factors that influence the recovery of hearing (age, gender, the amount of time between the onset of symptoms and the initiation of treatment – time since onset –, audiometric curve type and objective vertigo). Audiometric results were evaluated according to Siegel’s criteria. In patients treated also with hyperbaric oxygen therapy we observed complete resolution in 44.1% of the patients, partial resolution in 37.2%, slight improvement in 10.5% and no improvement in 8.2% of the patients. This resolution pattern was significantly different from that observed in the patients treated only with medical therapy. The factors associated with a better prognosis were young age, rapid intervention, upward sloping or pantonal audiometric patterns and the absence of objective vertigo. Gender appeared to be an insignificant factor. Medical treatment associated with hyperbaric oxygen therapy gives better results in terms of hearing gain compared to exclusive medical treatment.
Copyright (c) 2017 Filippo Ricciardiello, Teresa Abate, Annalisa Pianese, Massimo Mesolella, Flavia Oliva, Pierpaolo Ferrise, Giuseppe Cortese, Mariano Marmo, Romolo Villani, Marianna Abate, Salvatore Mazzone, Michele Cavaliere
The antioxidant mitochondrial protein UCP2 promotes cancer development connecting the Warburg effect and autophagy
Copyright (c) 2017 Marco Cordani, Giovanna Butera, Raffaella Pacchiana, Massimo Donadelli
Functional drug response assay for cancer stem cells in the era of precision medicine
Copyright (c) 2017 Candace M. Howard, Jagan Valluri, Pier Paolo Claudio