The Role of MN1-TEL, MN1 and TEL2 in Leukemia

Blood cells arise from a common totipotent hematopoietic stem cell after sequential differentiative steps in a process termed hematopoiesis. Abnormal proliferation along this process is crucial in the occurrence of leukemias. Understanding the relationships among cells of the hematopoietic system and the mechanisms underlying leukemogenesis constitutes a key priority of modern cancer research. The first goal of this thesis was to clarify the role of TEL2 in hematopoiesis and leukemogenesis. Our data show that TEL2 behaves as a bona fide oncogene in vivo, causing myeloproliferative disease (MPD) in mice. However, development of leukemia upon TEL2 overexpression requires cooperation of secondary mutations. Indeed, expressing TEL2 in Arf-/- bone marrow the onset of disease accelerates and phenotype shifts from MPD to B-cell lymphoma. Most importantly, we show that TEL2 directly regulates mTOR in Arf-/- pro-B cells, and propose a model whereby TEL2-dependent upregulation of mTOR is partly responsible for increased proliferation and survival rates of malignant cells, but must cooperate with additional growth-promoting signals dependent on TEL2 function. The second part of this thesis analyzes the role of MN1-TEL as hematopoietic oncogene, demonstrating its ability to cause myeloid malignance when expressed in murine bone marrow. These studies led us to discover that MN1 can per se stimulate the growth of mouse myeloid progenitors, causing MPD in mice. In addition we show that MN1 is upregulated in inv(16) AML patients, and when expressed in mice it cooperates with Cbfβ-SMMHC (the product of inv(16) rearrangements), leading to AML

Exposure to High Levels of Noise Poses Hazards and Risks for Development of Hypertension and Heart Disease: Potential Roles of Unrecognized Ionized Hypomagnesemia and Release of Ceramides and Platelet-Activating Factor

It has been demonstrated in numerous human and animal studies that audiogenic stress (AS) can induce elevation of arterial blood pressure and cardiac damage and that noise –induced hearing loss may be associated with alterations in magnesium (Mg) metabolism. Our laboratories, over a period of approximately 40 years, have been investigating why AS causes high blood pressure and cardiac damage. This review focuses on a number of newer discoveries on why AS causes dysfunctions of the cardiovascular system (CVS) This review discusses the pivotal physiological and biochemical importance of Mg to body health and the fact that most Americans and Europeans are deficient in daily Mg intake which perforce can cause severe dysfunctions of the CVS. Our ongoing studies clearly provide a solid microcirculatory basis for how and why AS above 65dB(A) often induces elevated blood pressure and cardiac damage. We review a body of data that points to the fact that AS does the latter, but appears to do so because noise stress levels result in Mg deficiency followed by release of certain sphingolipids (e.g., ceramides) and generation and release of platelet- activating factor (PDF). It is our opinion that all people exposed to high degrees of noise stress should be monitored for cardiovascular functions, ionized Mg levels, blood ceramide levels and levels of PDF. Lastly, we believe all people exposed to high levels of AS (i.e., maintenance people and pilots on aircraft carriers, musicians [particularly at rock concerts], motorman and conductors on trains and subways, construction site workers, etc.) should have at least the equivalent daily intake of 500-600 mg of Mg/day

Estimating sea surface temperature measurement methods using characteristic differences in the diurnal cycle

Lack of reliable observational metadata represents a key barrier to understanding sea surface temperature (SST) measurement biases, a large contributor to uncertainty in the global surface record. We present a method to identify SST measurement practice by comparing the observed SST diurnal cycle from individual ships with a reference from drifting buoys under similar conditions of wind and solar radiation. Compared to existing estimates, we found a larger number of engine room-intake (ERI) reports post War World II and in the period 1960 – 1980. Differences in the inferred mixture of observations lead to a systematic warmer shift of the bias adjusted SST anomalies from 1980 compared to previous estimates, while reducing the ensemble spread. Changes in mean field differences between bucket and ERI SST anomalies in the Northern Hemisphere over the period 1955 – 1995 could be as large as 0.5 °C and are not well reproduced by current bias adjustment models

Diagnostic accuracy of short-time inversion recovery sequence in Graves' ophthalmopathy before and after prednisone treatment

Introduction: In Graves' Ophthalmopathy, it is important to distinguish active inflammatory phase, responsive to immunosuppressive treatment, from fibrotic unresponsive inactive one. The purpose of this study is, first, to identify the relevant orbital magnetic resonance imaging signal intensities before treatment, so to classify patients according to their clinical activity score (CAS), discriminating inactive (CAS3) subjects and, second, to follow post-steroid treatment disease. Methods: An observational study was executed on 32 GO consecutive patients in different phases of disease, based on clinical and orbital Magnetic Resonance Imaging parameters, compared to 32 healthy volunteers. Orbital Magnetic Resonance Imaging was performed on a 1.5 tesla Magnetic Resonance Unit by an experienced neuroradiologist blinded to the clinical examinations. Results: In pre-therapy patients, compared to controls, a medial rectus muscle statistically significant signal intensity ratio (SIR) in short-time inversion recovery (STIR) (long TR/TE) sequence was found, as well as when comparing patients before and after treatment, both medial and inferior rectus muscle SIR resulted significantly statistically different in STIR. These increased outcomes explain the inflammation oedematous phase of disease, moreover after steroid administration, compared to controls; patients presented lack of that statistically significant difference, thus suggesting treatment effectiveness. Conclusion: In our study, we proved STIR signal intensities increase in inflammation oedematous phase, confirming STIR sequence to define active phase of disease with more sensibility and reproducibility than CAS alone and to evaluate post-therapy involvement. © 2014 Springer-Verlag

A Multicentre Study: The Use of Micrografts in the Reconstruction of Full-Thickness Posttraumatic Skin Defects of the Limbs - A Whole Innovative Concept in Regenerative Surgery

The skin graft is a surgical technique commonly used in the reconstructive surgery of the limbs, in order to repair skin loss, as well as to repair the donor area of the flaps and cover the dermal substitutes after engraftment. The unavoidable side effect of this technique consists of unaesthetic scars. In order to achieve the healing of posttraumatic ulcers by means of tissue regeneration and to avoid excessive scarring, a new innovative technology based on the application of autologous micrografts, obtained by Rigenera technology, was reported. This technology was able to induce tissue repair by highly viable skin micrografts of 80 micron size achieved by a mechanical disaggregation method. The specific cell population of these micrografts includes progenitor cells, which in association with the fragment of the Extracellular Matrix (ECM) and growth factors derived by patients' own tissue initiate biological processes of regeneration enhancing the wound healing process. We have used this technique in 70 cases of traumatic wounds of the lower and upper limbs, characterized by extensive loss of skin substance and soft tissue. In all cases, we have applied the Rigenera protocol using skin micrografts, achieving in 69 cases the complete healing of wounds in a period between 35 and 84 days. For each patient, the reconstructive outcome was evaluated weekly to assess the efficacy of this technique and any arising complication. A visual analogue scale (VAS) was administered to assess the amount of pain felt after the micrografts' application, whereas we evaluated the scars according to the Vancouver scale and the wound prognosis according to Wound Bed Score. We have thus been able to demonstrate that Rigenera procedure is very effective in stimulating skin regeneration, while reducing the outcome scar

The spectrum of thyroid dysfunction in an Australian hepatitis C population treated with combination Interferon-α2β and Ribavirin

BACKGROUND: The study aims to assess the pattern of thyroid response to combination Interferon-α2β (IFN-α) and Ribavirin (RBV) anti-viral therapy in an Australian hepatitis C cohort. These include the prevalence of thyroid dysfunction (TD) including hyperthyroidism and hypothyroidism and their possible predictors, the common overall pattern of thyroid function tests whilst receiving therapy and TD outcomes, and the correlation with HCV status outcome. METHODS: A retrospective analysis of all medical records was performed to assess thyroid function in Hepatitis C Virus (HCV) patients who were treated at the Hunter Area hepatitis C treatment center between 1995 and March 2004. The centre is part of the John Hunter hospital, a major tertiary referral centre in New South Wales, Australia. RESULTS: There were 272 cases available for review. The prevalence of TD is 6.7 percent and is made up predominantly of females (80 percent). There were 3 (1.1 percent) cases of hyperthyroidism with 2 (67 percent) females. Thirteen out of fifteen (80 percent) cases of hypothyroidism were females with the overall prevalence of 5.5 percent. The majority of hypothyroid patients still required Thyroxine supplement at the end of follow up. CONCLUSION: Ninety three percent of HCV treated patients have intact thyroid function at the end of treatment. The predominant TD is hypothyroidism. The predominant pattern of thyrotoxicosis (TTX) is that of thyroiditis although the number is small. Graves' like disease was not observed. People with pre-existing thyroid auto-antibodies should be closely monitored for thyroid dysfunction, particularly hypothyroidism

Minimally invasive mitral valve surgery: a systematic review.

In the recent years minimally invasive mitral valve surgery (MIMVS) has become a well-established and increasingly used option for managing patients with a mitral valve pathology. Nonetheless, whether the purported benefits of MIMVS translate into clinically important outcomes remains controversial. Therefore, in this paper we provide an overview of MIMVS and discuss results, morbidity, mortality, and quality of life following mitral minimally invasive procedures. MIMVS has been proven to be a feasible alternative to the conventional full sternotomy approach with low perioperative morbidity and short-term mortality. Reported benefits of MIMVS include also decreased postoperative pain, improved postoperative respiratory function, reduced surgical trauma, and greater patient satisfaction. Finally, compared to standard surgery, MIMVS demonstrated comparable efficacy across a range of long-term efficacy measures such as freedom from reoperation and long-term survival

High expression of glycolytic genes in Cirrhosis correlates with the risk of developing liver cancer

© 2018 Lee, Carella, Papa and Bubici. A marked increase in the rate of glycolysis is a key event in the pathogenesis of hepatocellular carcinoma (HCC), the main type of primary liver cancer. Liver cirrhosis is considered to be a key player in HCC pathogenesis as it precedes HCC in up to 90% of patients. Intriguingly, the biochemical events that underlie the progression of cirrhosis to HCC are not well understood. In this study, we examined the expression profile of metabolic gene transcripts in liver samples from patients with HCC and patients with cirrhosis. We found that gene expression of glycolytic enzymes is up-regulated in precancerous cirrhotic livers and significantly associated with an elevated risk for developing HCC. Surprisingly, expression levels of genes involved in mitochondrial oxidative metabolism are markedly increased in HCC compared to normal livers but remain unchanged in cirrhosis. Our findings suggest that key glycolytic enzymes such as hexokinase 2 (HK2), aldolase A (ALDOA), and pyruvate kinase M2 (PKM2) may represent potential markers and molecular targets for early detection and chemoprevention of HCC