Search

During cardiac differentiation, numerous factors contribute to the development of the heart. Understanding the molecular mechanisms underlying cardiac development will help combat cardiovascular disorders, among the leading causes of morbidity and mortality worldwide. Among the main mechanisms, we indeed find Cripto. Cripto is found in both the syncytiotrophoblast of ampullary pregnancies and the inner cell mass along the primitive streak as the second epithelial-mesenchymal transformation event occurs to form the mesoderm and the developing myocardium. At the same time, it is now known that cardiac signaling pathways are intimately intertwined with the expression of myomiRNAs, including miR-1. This miR-1 is one of the muscle-specific miRs; aberrant expression of miR-1 plays an essential role in cardiac diseases. Given this scenario, our study aimed to evaluate the inverse correlation between Cripto and miR-1 during heart development. We used in vitro models of the heart, represented by embryoid bodies (EBs) and embryonic carcinoma cell lines derived from an embryo-derived teratocarcinoma in mice (P19 cells), respectively. First, through a luciferase assay, we demonstrated that Cripto is a target of miR-1. Following this result, we observed that as the days of differentiation increased, the Cripto gene expression decreased, while the level of miR-1 increased; furthermore, after silencing miR-1 in P19 cells, there was an increase in Cripto expression. Moreover, inducing damage with a cobra cardiotoxin (CTX) in post-differentiation cells, we noted a decreased miR-1 expression and increased Cripto. Finally, in mouse cardiac biopsies, we observed by monitoring gene expression the distribution of Cripto and miR-1 in the right and left ventricles. These results allowed us to detect an inverse correlation between miR-1 and Cripto that could represent a new pharmacological target for identifying new therapies.

Malignant melanoma still remains a cancer with very poor survival rates, although it is at the forefront of personalized medicine. Most patients show partial responses and disease progressed due to adaptative resistance mechanisms, preventing long-lasting clinical benefits to the current treatments. The response to therapies can be shaped by not only taking into account cancer cell heterogeneity and plasticity, but also by its structural context as well as the cellular component of the tumor microenvironment (TME). Here, we review the recent development in the field of immunotherapy and target-based therapy and how, in the era of tumor micro-tissue engineering, ex-vivo assays could help to enhance our melanoma biology knowledge in its complexity, translating it in the development of successful therapeutic strategies, as well as in the prediction of therapeutic benefits.

Melanoma is the less common but the most malignant skin cancer. Since the survival rate of melanoma metastasis is about 10-15%, many different studies have been carried out in order to find a more effective treatment. Although the development of target-based therapies and immunotherapeutic strategies has improved chances for patient survival, melanoma treatment still remains a big challenge for oncologists. Here, we collect recent data about the emerging role of melanoma-associated microRNAs (miRNAs) currently available treatments, and their involvement in drug resistance. We also reviewed miRNAs as prognostic factors, because of their chemical stability and resistance to RNase activity, in melanoma progression. Moreover, despite miRNAs being considered small conserved regulators with the limitation of target specificity, we outline the dual role of melanoma-associated miRNAs, as oncogenic and/or tumor suppressive factors, compared to other tumors., Competing Interests: The authors declare no conflict of interest.

Collagen prolyl hydroxylation (CPH), which is catalyzed by prolyl 4-hydroxylase (P4H), is the most prevalent posttranslational modification in humans and requires vitamin C (VitC). Here, we demonstrate that CPH acts as an epigenetic modulator of cell plasticity. Increased CPH induced global DNA/histone methylation in pluripotent stem and tumor cells and promoted cell state transition (CST). Interfering with CPH by either genetic ablation of P4H subunit alpha-2 (P4HA2) or pharmacologic treatment reverted epigenetic changes and antagonized CST. Mechanistically, we suggest that CPH modifies the epigenetic landscape by reducing VitC for DNA and histone demethylases. Repurposed drugs targeting CPH-mediated metabolic perturbation, such as the antiasthmatic budesonide, blocked metastatic dissemination of breast cancer cells in vivo by preventing mesenchymal transition. Our study provides mechanistic insights into how metabolic cues and epigenetic factors integrate to control CST and paves the way for the development of novel antimetastatic strategies. SIGNIFICANCE: A phenotype-based high-throughput screening reveals unforeseen metabolic control of cell plasticity and identifies budesonide as a drug candidate for metastatic cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/13/3235/F1.large.jpg., (©2019 American Association for Cancer Research.)

In the last ten years we assisted to spreading of laparoscopic approach on the correction of median incisional hernia, although for increased interesting toward mini-invasive techniques than for matching results between lap and open approaches. The aim of our study is the critical analysis of the results of lap and open surgery in the approach of ventral hernia, through the meta-analytical revision of the principal checked prospective trials. There were emerged 7 perspective studies to fit to a meta-analysis with the revision of the literature, with 1165 patients in total. Among the perioperative outcomes the briefer surgical time and a reduction of postoperative hospitalization were observed with the significant statistic data in favor of the lap. Laparoscopy can be considered a valid technical alternative to traditional open surgery in the treatment of ventral incisional hernia. The advantages of mini-invasive approach are the reducing of the surgical time and of the total hospital stay. There were not emerged any significant differences regarding the other surgical end-points or the recurrences of hernias after 1 and 5 years.

The number of short-stay surgery procedures has progressively increased since the concept of short-stay surgery was first introduced. Initially this type of surgery was reserved for patients undergoing inguinal hernia repair, proctological surgery, and various minor procedures. Careful patient selection makes it possible to apply one-day surgery to other surgical specialties including breast cancer surgery. Reducing the length of hospital stay lowers health care costs, and shortens waiting lists. The most important benefits for patients are a more rapid return to work and positive psychological effects. Exclusion criteria for one-day surgery are the lack of home care, excessive distance from place of treatment and the presence of any concomitant pathology that is a contraindication to this type of surgery. We report our experience in oncological surgery of the breast in one-day surgery.

Objectives: This study sought to identify proteins from the cardiomyocyte (CM) secretome that are directly targeted by the muscle-specific microRNA-1 (miR-1), and thus reflect the pathophysiological state of the CM., Background: MicroRNAs play critical regulatory roles during myocardial remodeling and progression to heart failure. However, it remains unknown whether secreted microRNA-targeted proteins can be used as indicators of myocardial microRNA expression and function., Methods: A proteomic analysis based on multidimensional protein identification technology was performed on supernatants from cultured CMs overexpressing miR-1. Biochemical assays and an inducible cardiac-specific transgenic mouse model overexpressing miR-1 were used to demonstrate that heart-type fatty acid-binding protein-3 (FABP3) is a target of miR-1. Levels of miR-1 and FABP3 in cardiac tissue and plasma samples from mouse models as well as human patients were quantified by quantitative reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The study included wild-type mice subjected to ventricular pressure overload or fasting, as well as patients diagnosed with ventricular hypertrophy due to valvular aortic stenosis, acromegaly, or growth hormone deficiency, conditions associated with altered miR-1 expression., Results: An inverse relationship between myocardial expression of miR-1 and circulating levels of FABP3 was found both in vitro and in vivo under various pathological conditions., Conclusions: Assessment of FABP3 plasma levels in human patients might be used for indirectly measuring cardiac miR-1 activity., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The AA report a case of a patient with acute abdomen caused by intestinal Anisakiasis, a fish-transmitted infection that results from ingestion of raw or improperly cooked fish contaminated by live larvae of Anisakis Simplex, a round worm from the order of Ascaridida., Material and Methods: A 33-year-old man, presented to the emergency room with severe upper abdominal pain, nausea and vomiting, without fever. The patient revealed that he had eaten pickled anchovies a few days before., Results: On the exploratory laparotomy an edematous and stenotic tract of 15 cm of jejunum was found, and a segmental resection was performed. Histologically, the resected jejunum showed a conspicuous and diffuse inflammatory infiltration, predominantly made up of eosinophil granulocytes, numerous mucosal erosions and the presence in the submucosa of sections of parasites which were identified as Anisakis Simplex larvae., Discussion: The ingestion of fish contaminated by Anisakis larva is often followed by the appearance of systemic or gastrointestinal symptoms due respectively to the direct larva localization and the allergic reaction to some parasite components. Diagnosis is made frequently difficult by clinical manifestations that could mimic symptoms of other diseases more common in Italy., Conclusions: Globalization has made Anisakiasis a more and more frequent disease worldwide, as increased mixture of different cultures and international travelling has allowed the spreading of risky feeding habits. That's why Anisakiasis should be considered in differential diagnosis of intestinal obstruction in patients with positive anamnesis for suspiciously cooked or conserved seafood eating.

Objective: Ileal carcinoids diagnosis, generally, is late because patients have aspecific symptoms., Material of Study: The two cases described presented for a long time peristaltic abdominal pains, vomit episodes and reduction of weight, with negativity of radiologic reports. The first diagnosis was adhesion syndrome produced by previous abdominal surgical operation; just emergency surgical operation executed for intestinal occlusion noticed carcinoids, located into the distal ileum, which infiltrated muscular wall and interested regional lymph nodes., Results: Ileal carcinoids diagnosis, generally, takes place during emergency laparotomy for intestinal occlusion which is the most frequent complication of this tumor. At the moment of diagnosis the tumor presents an advanced stage of evolution., Discussion: Ileal carcinoids behave malignant because of their biologic aggressiveness and because of at the moment of diagnosis they present an advanced stage of evolution. Symptomatology is aspecific, just a carcinoid syndrome could addressed clinical diagnosis, but this is an rare event and however it needs of liver metastases to appear. In case there is an clinical suspect scintigraphy with Octreoscan can locate tumor and metastases., Conclusions: Surgical treatment of ileal carcinoids is based on large resections en bloc. Ileal carcinoids survival to 5 years is estimated inferior to 60% after surgical treatment.

Myc is a well known proto-oncogene encoding for a transcription factor whose activity is tightly regulated in the cellular context. Myc was the first oncogene recognized to activate the ARF tumor suppressor gene which suppresses cell proliferation partly through stabilization of the p53 tumor suppressor protein but which also has p53-independent growth-suppressive functions. Recent studies have indicated that mouse p19ARF negatively regulates Myc's transcriptional activity. We here show that the human p14ARF directly associates with Myc and relocates Myc from the nucleoplasm to the nucleolus. We found that p14ARF interacts with the Myc-Max complex and the binding of p14ARF does not interfere with Myc-Max interaction in vitro. Protein interaction assays define the Myc BoxII as a critical domain required for interaction with p14ARF. Moreover, we identify 30 amino acids encompassing Myc BoxII domain required for p14ARF interaction and colocalization in vivo. Finally, we show that p14ARF down regulates Myc activated transcription and that this activity cannot be addressed to an intrinsic p14ARF repressor domain.

Background: The positive transcription elongation factor b (P-TEFb) composed by CDK9/CyclinT1 subunits is a dedicated co-factor of HIV transcriptional transactivator Tat protein. Transcription driven by the long terminal repeat (LTR) of HIV involves formation of a quaternary complex between P-TEFb, Tat and the TAR element. This recruitment is necessary to enhance the processivity of RNA Pol II from the HIV-1 5' LTR promoter. The activity of P-TEFb is regulated in vivo and in vitro by the HEXIM1/7SK snRNA ribonucleic-protein complex., Results: Here we report that Tat transactivation is effectively inhibited by co-expression of HEXIM1 or its paralog HEXIM2. HEXIM1 expression specifically represses transcription mediated by the direct activation of P-TEFb through artificial recruitment of GAL4-CycT1. Using appropriate HEXIM1 mutants we determined that effective Tat-inhibition entails the 7SK snRNA basic recognition motif as well as the C-terminus region required for interaction with cyclin T1. Enhanced expression of HEXIM1 protein modestly affects P-TEFb activity, suggesting that HEXIM1-mediated repression of Tat activity is not due to a global inhibition of cellular transcription., Conclusion: These results point to a pivotal role of P-TEFb for Tat's optimal transcription activity and suggest that cellular proteins that regulate P-TEFb activity might exert profound effects on Tat function in vivo.