Transcriptional activation of the miR-17-92 cluster is involved in the growth-promoting effects of MYB in human Ph-positive leukemia cells.

MicroRNAs, non-coding regulators of gene expression, are likely to function as important downstream effectors of many transcription factors including MYB. Optimal levels of MYB are required for transformation/maintenance of BCR-ABL-expressing cells. We investigated whether MYB silencing modulates microRNA expression in Philadelphia-positive (Ph+) leukemia cells and if MYB-regulated microRNAs are important for the MYB addiction of these cells. Thirty-five microRNAs were modulated by MYB silencing in lymphoid and erythromyeloid chronic myeloid leukemia-blast crisis BV173 and K562 cells; 15 of these were concordantly modulated in both lines. We focused on the miR-17-92 cluster because of its oncogenic role in tumors and found that: i) it is a direct MYB target; ii) it partially rescued the impaired proliferation and enhanced apoptosis of MYB-silenced BV173 cells. Moreover, we identified FRZB, a Wnt/β-catenin pathway inhibitor, as a novel target of the miR-17-92 cluster. High expression of MYB in blast cells from 2 Ph+leukemia patients correlated positively with the miR-17-92 cluster and inversely with FRZB. This expression pattern was also observed in a microarray dataset of 122 Ph+acute lymphoblastic leukemias. In vivo experiments in NOD scid gamma mice injected with BV173 cells confirmed that FRZB functions as a Wnt/β-catenin inhibitor even as they failed to demonstrate that this pathway is important for BV173-dependent leukemogenesis. These studies illustrate the global effects of MYB expression on the microRNAs profile of Ph+cells and supports the concept that the MYB addiction of these cells is, in part, caused by modulation of microRNA-regulated pathways affecting cell proliferation and survival. Copyright© 2019 Ferrata Storti Foundation

Correlates of spinal deforming index (SDI) in HIV-positive patients naive and on treatment

Methods HIV-infected subjects naive or on stable HAART were included. Vertebral deformities were identified using SDI (according to semiquantitative method by Genant), calculated by summing the deformity grades of all vertebrae (T4 to L4); pathological deformities are defined as follow: grade 1 between 20–25%, grade 2 between 26–40%, and grade 3 > >40%. According to WHO criteria, osteopenia and osteoporosis were diagnosed in patients having spine BMD calculated as -1 << T-score << -2.5 and T-score ≤≤2.5, respectively. The correlation between SDI and spine BMD was evaluated by univariate and multivariate linear regression. [Other variables considered: gender, age, current CD4 count, CD4 nadir, BMI, lipid parameters, alcohol intake, smoking habit, physical activity, family history for bone fracture, months of ARV exposure, and co-infection with hepatitis viruses; only the variables with p <<0.2 in univariate analyses were included in the final model.

Clinical and instrumental assessment of herniated discs after nucleoplasty: A preliminary study

Background and Aim: The therapy for low back pain boasts different approaches; one of these is nucleoplasty. We wanted to assess the effectiveness of nucleoplasty both by clinical response both by MR imaging evaluation, including even extrusions larger than one third of the spinal canal. Methods: Fifty-seven patients were treated with nucleoplasty in our hospital, 11 of these patients accepted both clinical and MRI evaluation after six months from treatment. The clinical evaluation was performed with Visual Analogue Scale (VAS) of pain, scored before and after the procedure. MRI evaluation consisted of analysing some imaging parameters of disc protrusions before and after the treatment. Results: In 10 out of 11 (91%) patients, VAS was reduced and only 1 out of 11 (9%) had the same pain after procedure. The mean of decrease of VAS score was 64%. In our population 8/11 (72%) patients had a herniation larger than 1/3 of the sagittal diameter of spinal canal and 100% of them had an improvement with a mean VAS reduction value of 75%. With MRI evaluation, the mean percentage of expulsion before and after treatment was respectively 40% and 34%. The expulsion decreased in 7/13 discs, remained equal in 4/13, and increased in 2/13 discs. Among the 9 larger protrusions, 3 didn\u2019t change, 6 reduced with a decrease mean value of 13%. Other MRI parameters didn\u2019t change significantly. Conclusions: Our preliminary experience supports the success of coblation on pain relief, aiming to show progressively that this treatment is suitable even in case of great extrusions, which are generally treated only with surgical approach. It\u2019s not clear the usefulness of MRI control yet, even if in most of cases we could have found a certain reduction of expulsion degree

Doxorubicin upregulates CXCR4 via miR-200c/ZEB1-dependent mechanism in human cardiac mesenchymal progenitor cells.

Doxorubicin (DOXO) treatment is limited by its cardiotoxicity, since it causes cardiac-progenitor-cell depletion. Although the cardioprotective role of the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 (SDF1/CXCR4) axis is well established, its involvement during DOXO-induced cardiotoxicity has never been investigated. We showed that in a mouse model of DOXO-induced cardiomyopathy, CXCR4 &lt;sup&gt;+&lt;/sup&gt; cells were increased in response to DOXO, mainly in human cardiac mesenchymal progenitor cells (CmPC), a subpopulation with regenerative potential. Our in vitro results showed a CXCR4 induction after 24 h of DOXO exposure in CmPC. SDF1 administration protected from DOXO-induced cell death and promoted CmPC migration. CXCR4 promoter analysis revealed zinc finger E-box binding homeobox 1 (ZEB1) binding sites. Upon DOXO treatment, ZEB1 binding decreased and RNA-polymerase-II increased, suggesting a DOXO-mediated transcriptional increase in CXCR4. Indeed, DOXO induced the upregulation of miR-200c, that directly targets ZEB1. SDF1 administration in DOXO-treated mice partially reverted the adverse remodeling, decreasing left ventricular (LV) end diastolic volume, LV ejection fraction and LV anterior wall thickness in diastole, recovering LV end systolic pressure and reducing±dP/dt. Moreover, in vivo administration of SDF1 partially reverted DOXO-induced miR-200c and p53 protein upregulation in mouse hearts. In addition, downmodulation of ZEB1 mRNA and protein by DOXO was significantly increased by SDF1. In keeping, p21 mRNA, that is induced by p53 and inhibited by ZEB1, is induced by DOXO treatment and is decreased by SDF1 administration. This study showed new players of the DOXO-induced cardiotoxicity, that can be exploited to ameliorate DOXO-associated cardiomyopathy

Virtual dissection by ultrasound: probe handling in the first year of medical education

Objectives The aim of the present study was to assess the educational plan of first-year students of medicine by analyzing their scores in ultrasound body scanning. Methods Since 2009, the San Paolo Medical School (Milan, Italy) has vertically integrated the study of anatomy with ultrasound-assisted virtual body dissection. Three modules were supplied: musculoskeletal system, heart and abdomen pelvis. 653 first-year students were trained. The students alternated as mutual model and operator. A skillfulness score was assigned to each student. The scores were consequently listed. Nonparametric exact multiple contrast tests were employed to determine relative group effects. Results Statistical analysis showed that: no gender-related differences were found (0:49; p = 0.769); peer learners performed less well than peer tutors (0.677; p = 0); between modules, scores in the musculoskeletal system (pMS = 0.726) tend to be higher (p < 0.001) than those obtained in the heart and abdomen pelvis (pH = 0.398; pAP = 0.375 p = 0.270); significant differences were found compared to the beginning of the project\u2019s academic year. Conclusion The students considered this didactic course an engaging and exciting approach. Acceptance of peer teaching was extraordinarily high. Autonomous exercitation allowed the students to improve self-criticism and enhance their own skills. The level of expertise obtained by peer tutors and by peer learners can be considered satisfactory. The main objective of training future physicians on personal stethoechoscope with the necessary competence seems to have been successfully started

Ultrasound approach as integration of gross anatomy educational path for medical students

For physicians, the human body is the focus of investigation and intervention on a daily basis. It follows that the study of anatomy will continue to be essential to safe medical practice [1]. Anatomical education represents the cultural path that includes the best coexistence of old techniques, and avant-garde. Thus teachers forming future physicians are imposed to find new strategies for the acquisition of adequate professional competences [2]. The gross anatomy course attended by medical students was integrated by ultrasound training. Students were trained either in palpating and recognizing surface body-landmarks, or in the detection of different viscera. Their abilities were then evaluated. For three academic years (since 2009-10 to 2011-12), all the 262 students enrolled in the first year of Medicine and Surgery degree (\u201cSan Paolo\u201d Hospital, Universit\ue0 degli Studi di Milano, Italy) participated. Of them, 16 volunteered in 2009-10, and 17 in each of the next two years, to preliminarily attend ultrasound training that their fellows would attend later. After this preliminary training, volunteers tutored their course fellows as peer tutors. All participants were either models or users. Each training presented three modules: 1) information about ultrasound scanning; 2) musculoskeletal system, major arterial and venous vessels, major nervous trunks, thyroid gland; 3) most thoracic, abdominal and pelvic viscera. Modules 2 and 3 were attended by small groups (6 students, assisted by 2 peer tutors). In module 2, topographical anatomy and subsequent recognition and palpation of surface bodylandmarks were also taught. The study of musculoskeletal system, major vessels and nerve trunks, and thyroid gland was supported by a multi-frequency probe equipped ultrasound machine. Thoracic, abdominal, and pelvic viscera were explored by a new generation pocket-sized ultrasound machine. Acquired skills were verified. The levels of expertise obtained by peer tutors and students were generally satisfactory. Students understood the importance of operative knowledge in human anatomical context. Anatomists found a valid method to consolidate the professionalizing quality of the topic

An open label pilot trial of low‐dose lithium for young people at ultra‐high risk for psychosis

Aim: Lithium, even at low doses, appears to offer neuroprotection against a wide variety of insults. In this controlled pilot, we examined the safety (i.e., side‐effect profile) of lithium in a sample of young people identified at ultra‐high risk (UHR) for psychosis. The secondary aim was to explore whether lithium provided a signal of clinical efficacy in reducing transition to psychosis compared with treatment as usual (TAU). Methods: Young people attending the PACE clinic at Orygen, Melbourne, were prescribed a fixed dose (450 mg) of lithium (n = 25) or received TAU (n = 78). The primary outcome examined side‐effects, with transition to psychosis, functioning and measures of psychopathology assessed as secondary outcomes. Results: Participants in both groups were functionally compromised (lithium group GAF = 56.6; monitoring group GAF = 56.9). Side‐effect assessment indicated that lithium was well‐tolerated. 64% (n = 16) of participants in the lithium group were lithium‐adherent to week 12. Few cases transitioned to psychosis across the study period; lithium group 4% (n = 1); monitoring group 7.7% (n = 6). There was no difference in time to transition to psychosis between the groups. No group differences were observed in other functioning and symptom domains, although all outcomes improved over time. Conclusions: With a side‐effect profile either comparable to, or better than UHR antipsychotic trials, lithium might be explored for further research with UHR young people. A definitive larger trial is needed to determine the efficacy of lithium in this cohort

Rosiglitazone as an option for patients with acromegaly: a case series

<p>Abstract</p> <p>Introduction</p> <p>In the patient with acromegaly, pituitary surgery is the therapeutic standard. Despite undergoing surgery, a significant number of patients with acromegaly continue to have uncontrolled growth hormone secretion. These patients require other treatments such as external irradiation and/or drug therapy.</p> <p>Case presentation</p> <p>We present the clinical and laboratory responses to six months of treatment with rosiglitazone in four cases. In all four cases, the patients had persistent growth hormone overproduction despite previous surgical treatment and other conventional therapy. Case 1 is a 57-year-old Caucasian woman, case 2 is a 51-year-old Hispanic man, case 3 is a 32-year-old Hispanic woman, and case 4 is a 36-year-old Hispanic man. In three of these patients, basal and nadir growth hormone and insulin-like growth factor 1 levels were significantly decreased (<it>P </it>< 0.05 and <it>P </it>< 0.01, respectively).</p> <p>Conclusion</p> <p>Rosiglitazone could be a treatment option in select patients with acromegaly.</p

CREB Is Activated by Muscle Injury and Promotes Muscle Regeneration

The cAMP response element binding protein (CREB) plays key roles in differentiation of embryonic skeletal muscle progenitors and survival of adult skeletal muscle. However, little is known about the physiologic signals that activate CREB in normal muscle. Here we show that CREB phosphorylation and target genes are induced after acute muscle injury and during regeneration due to genetic mutation. Activated CREB localizes to both myogenic precursor cells and newly regenerating myofibers within regenerating areas. Moreover, we found that signals from damaged skeletal muscle tissue induce CREB phosphorylation and target gene expression in primary mouse myoblasts. An activated CREB mutant (CREBY134F) potentiates myoblast proliferation as well as expression of early myogenic transcription factors in cultured primary myocytes. Consistently, activated CREB-YF promotes myoblast proliferation after acute muscle injury in vivo and enhances muscle regeneration in dystrophic mdx mice. Our findings reveal a new physiologic function for CREB in contributing to skeletal muscle regeneration