Cyclin dependent kinase 4 and 6 inhibitors as novel therapeutic agents for targeted treatment of malignant mesothelioma

Malignant Mesothelioma (MM) is a rare and aggressive form of tumour that affects the lining of the internal organs for which current treatments have not been proven to be very effective. P16(INK4A) tumour suppressor encoding CDKN2A gene is often downregulated in MM. This protein is a cyclin dependent kinase 4 and 6 inhibitor, that normally phosphorylates RB1, which has to be un-phosphorylated in order to block cell-cycle at G1 in normal cells. Adding CDK inhibitor molecules to MM in pre-clinical studies has been proven to restore the normal function of p16(INK4A), blocking thereby MM cell cycle at G1. Future randomised phase III studies with CDK4/6 inhibitors in MM carrying relevant CDK4/6, cyclin D1/3 or p16 aberrations will be warranted

Metastatic angioimmunoblastic T-cell lymphoma started from thoracic paravertebral region: a Case report

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most frequent nodal T-cell lymphoma. 1,2 It derives from follicular helper T-cell (TFH).3 It accounts for 15 - 20% of all peripheral T-cell lymphomas and usually affects patients in the seventh decade of life.1,2,4,5 AITL\u2019s incidence is nearly 0,05 new patient case per 100,000 people in US, and there\u2019s no sex predilection.6,7 It is characterized by polymorphic lymph node infiltrate with a prominent proliferation of high endothelial venules and follicular dendritic cells, different immune disorders and a poor prognosis. 8,9 The neoplastic T-cells express CD2, CD3, CD4 and CD10 but the marker\u2019s specificity has been debated. More specific indicators of AITL are CXCL-13, programmed death-1 (PD1), inducible costimulator (ICOS), and BCL6 transcription factor.10-12 Nearly all patients have EBV-infected B cells in their lymph nodes, but the presence of these EBV-positive cells doesn\u2019t correlate with survival.13-15 However, the role of EBV isn\u2019t clear yet: it could be secondary to the immune deregulation, or it could be a fundamental factor involved in disease\u2019s start and progression. AITL is frequently associated with polyclonal B-cell or plasma cell proliferation;8 this neoplastic proliferation of B-cells on parallel with AITL could be motivated by a cluster of pluripotent cells with the ability to differentiate into B-cells and T-cells neoplasm simultaneously, maybe due to exposition to pharmacological therap\ue8ies or specific mutagens. Clinical manifestations are often represented by group-B symptoms (fever, night sweats, weight loss), hepatosplenomegaly, anemia, lymphadenopathy, polyclonal hypergammaglobulinemia, thrombocytopenia and/or a large variety of immune disorders.16,17 Up to 50% of develop cutaneous lesions, expression of extranodal diffusion of the tumor: urticaria, purpura, pruritic maculopapular eruptions, erosions, plaques, nodules, petechiae.18-20 Despite occasionally spontaneous remissions,21 AITL prognosis is poor, with a median overall survival of 3 years

Evaluation of region selective bilirubin-induced brain damage as a basis for a pharmacological treatment

The neurologic manifestations of neonatal hyperbilirubinemia in the central nervous system (CNS) exhibit high variations in the severity and appearance of motor, auditory and cognitive symptoms, which is suggestive of a still unexplained selective topography of bilirubin-induced damage. By applying the organotypic brain culture (OBC: preserving in vitro the cellular complexity, connection and architecture of the in vivo brain) technique to study hyperbilirubinemia, we mapped the regional target of bilirubin-induced damage, demonstrated a multifactorial toxic action of bilirubin, and used this information to evaluate the efficacy of drugs applicable to newborns to protect the brain. OBCs from 8-day-old rat pups showed a 2-13 fold higher sensitivity to bilirubin damage than 2-day-old preparations. The hippocampus, inferior colliculus and cerebral cortex were the only brain regions affected, presenting a mixed inflammatory-oxidative mechanism. Glutamate excitotoxicity was appreciable in only the hippocampus and inferior colliculus. Single drug treatment (indomethacin, curcumin, MgCl2) significantly improved cell viability in all regions, while the combined (cocktail) administration of the three drugs almost completely prevented damage in the most affected area (hippocampus). Our data may supports an innovative (complementary to phototherapy) approach for directly protecting the newborn brain from bilirubin neurotoxicity

Breastfeeding: a reproductive factor able to reduce the risk of luminal B breast cancer in premenopausal White women

In the medical literature, the role of breastfeeding and reproductive factors in the risk of breast carcinoma is still an open debate in premenopausal women. We highlight the role of breastfeeding and reproductive factors in luminal A and luminal B, the most frequent breast cancers. This case-control study analyzes a White premenopausal population of 286 breast cancer patients, divided into molecular subtypes, and 578 controls matched by age. Multivariate logistic regression models were used to assess the relationships of breastfeeding and other reproductive factors (age at menarche, parity, age at first pregnancy, number of children) with the risk of breast cancers. Among the variables examined, reproductive factors did not alter the risk of cancer, whereas breastfeeding up to 12 months was a significant protective factor against luminal B breast cancer (multivariate odds ratio: 0.22, 95% confidence interval: 0.09-0.59, P=0.002). In contrast, luminal A cases did not significantly correlate with breastfeeding or other reproductive factors. Breastfeeding up to 12 months is strongly protective against the more aggressive luminal B, but not against the less aggressive luminal A breast cancer in premenopausal White women

Radiofrequency ablation for benign thyroid nodules

Benign thyroid nodules are an extremely common occurrence. Radiofrequency ablation (RFA) is gaining ground as an effective technique for their treatment, in case they become symptomatic. Here we review what are the current indications to RFA, its outcomes in terms of efficacy, tolerability, and cost, and also how it compares to the other conventional and experimental treatment modalities for benign thyroid nodules. Moreover, we will also address the issue of treating with this technique patients with cardiac pacemakers (PM) or implantable cardioverter-defibrillators (ICD), as it is a rather frequent occurrence that has never been addressed in detail in the literature

GT75 aptamer against eukaryotic elongation factor 1A as potential anticancer drug for castrate-resistant prostate cancer (CRPC).

Prostate cancer diagnosis is increasing, being the second most frequently cancer in men worldwide. The treatment of castrate-resistant prostate cancer is often unsuccessfully and new therapeutic interventions are searching for. Nucleic acid aptamers targeting eEF1A proteins are emerging molecular tools for the control of cancer growth. We found that an aptamer named GT75 was able to bind to eEF1A proteins of human prostate cancer cell lines and to significantly and specifically reduce their growth with respect to the control oligomer CT75. The highest anti-proliferation effect was found in the androgen-independent PC-3 cells. Interestingly, GT75 was able to specifically inhibit the migration of PC-3 cells but not that of the nontumorigenic PZHPV-7 cells. The overall results suggest that the GT75 aptamer targeting eEF1A proteins is a promising molecular drug to develop for the control of the castrate-resistant prostate cance

Cutaneous melanoma frequencies and seasonal trend in 20 years of observation of a population characterised by excessive sun exposure

Background: Cutaneous melanoma is an aggressive form of skin cancer. It has become an increasingly common neoplasm in the most developed countries, especially among individuals of European origin. Methods: Anonymous data of patients with cutaneous melanoma were collected from the diagnostic database of the University Hospital of Trieste from 1 January 1990 to 10 December 2013. Our study is based on a population which was constant over the period of observation; it was also well-defined and characterised by unrestrained sun exposure. Results: The number of cutaneous melanomas increased during the period of observation with a seasonality trend and gender related differences both for anatomical sites distribution and stage of the disease. Moreover, 6% of our cohort developed multiple melanomas. Conclusions: In a well-defined population devoted to excessive sun exposure the frequencies of skin melanomas roughly doubled from 1990 to 2013 following a seasonal trend. In that population, prevention efforts according to gender specific risk behaviour, as well as follow-up programmes both for evaluation of metastatic spreading and for early diagnosis of additional skin melanomas, are crucial due to gender specific differences and to the occurrence of multiple melanomas

A simplified edge illumination set-up for quantitative phase contrast mammography with synchrotron radiation at clinical doses

This work presents the first study of x-ray phase contrast imaging based on a simple implementation of the edge illumination method (EIXPCi) in the field of mammography with synchrotron radiation. A simplified EIXPCi set-up was utilized to study a possible application in mammography at clinical doses. Moreover, through a novel algorithm capable of separating and quantifying absorption and phase perturbations of images acquired in EIXPCi modality, it is possible to extract quantitative information on breast images, allowing an accurate tissue identification. The study was carried out at the SYRMEP beamline of Elettra synchrotron radiation facility (Trieste, Italy), where a mastectomy specimen was investigated with the EIXPCi technique. The sample was exposed at three different energies suitable for mammography with synchrotron radiation in order to test the validity of the novel algorithm in extracting values of linear attenuation coefficients integrated over the sample thickness. It is demonstrated that the quantitative data are in good agreement with the theoretical values of linear attenuation coefficients calculated on the hypothesis of the breast with a given composition. The results are promising and encourage the current efforts to apply the method in mammography with synchrotron radiation

Cell-free DNA integrity for the monitoring of breast cancer: Future perspectives?

Breast cancer (BC) is the most common cancer and the second cause of death in women worldwide. Therapeutic options are increasing, but the response to treatments is not always efficient and the risk of recurrence covers decades. In this perspective, the need to have a proper follow-up for the therapeutic responses and for anticipating recurrence it is urgent in the clinical setting. Liquid biopsy provides the basic principle for a non-invasive method for the routinely monitoring of BC. However, due to the heterogeneity of tumors during onset and progression, the search for tumor DNA mutations of targeted genes in plasma/serum is a limiting factor. A possible approach overtaking this problem comes from the measurement of cell-free DNA integrity, which is an independent factor from the mutational status and theoretically is representative of all tumors. This review summarizes the state-of-the-art of cell-free DNA integrity researches in BC, the controversies and the future perspective

Current Status of Fibroblast Growth Factor Receptor-Targeted Therapies in Breast Cancer

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is an urgent need for better knowledge of the biology leading to the disease, which can lead to the design of increasingly accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the fibroblast growth factor receptor (FGFR) pathway, triggered by specific ligands. The Fibroblast Growth Factor Receptors/Fibroblast Growth Factors (FGFRs/FGFs) axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of FGFR mutations, which lead to tumor formation and summarizes the state-of-the-art therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC