Direct reprogramming of adult somatic cells into other lineages: past evidence and future perspectives

Direct reprogramming of an adult cell into another differentiated lineage-such as fibroblasts into neurons, cardiomyocytes, or blood cells-without passage through an undifferentiated pluripotent stage is a new area of research that has recently emerged alongside stem cell technology and induced pluripotent stem cell reprogramming; indeed, this avenue of investigation has begun to play a central role in basic biology research and regenerative medicine. Even though the field seems new, its origins go back to the 1980s when it was demonstrated that differentiated adult cells can be converted into another cell lineage through the overexpression of transcription factors, establishing mature cell plasticity. Here, we retrace transdifferentiation experiments from the discovery of master control genes to recent in vivo reprogramming of one somatic cell into another from the perspective of possible applications for the development of new therapeutic approaches for human diseases

STIM1 R304W in mice causes subgingival hair growth and an increased fraction of trabecular bone

Calcium signaling plays a central role in bone development and homeostasis. Store operated calcium entry (SOCE) is an important calcium influx pathway mediated by calcium release activated calcium (CRAC) channels in the plasma membrane. Stromal interaction molecule 1 (STIM1) is an endoplasmic reticulum calcium sensing protein important for SOCE. We generated a mouse model expressing the STIM1 R304W mutation, causing Stormorken syndrome in humans. Stim1R304W/R304W mice showed perinatal lethality, and the only three animals that survived into adulthood presented with reduced growth, low body weight, and thoracic kyphosis. Radiographs revealed a reduced number of ribs in the Stim1R304W/R304W mice. Microcomputed tomography data revealed decreased cortical bone thickness and increased trabecular bone volume fraction in Stim1R304W/R304W mice, which had thinner and more compact bone compared to wild type mice. The Stim1R304W/+ mice showed an intermediate phenotype. Histological analyses showed that the Stim1R304W/R304W mice had abnormal bone architecture, with markedly increased number of trabeculae and reduced bone marrow cavity. Homozygous mice showed STIM1 positive osteocytes and osteoblasts. These findings highlight the critical role of the gain-of-function (GoF) STIM1 R304W protein in skeletal development and homeostasis in mice. Furthermore, the novel feature of bilateral subgingival hair growth on the lower incisors in the Stim1R304W/R304W mice and 25 % of the heterozygous mice indicate that the GoF STIM1 R304W protein also induces an abnormal epithelial cell fate

Colocalization of ribonuclear inclusions with muscle blind like-proteins in a family with myotonic dystrophy type 2 associated with a short CCTG expansion

Myotonic dystrophy type 2 (DM2) is an autosomal dominant multisystemic disorder caused by a CCTG repeat expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene. We present a three first-degree relative Italian family (proband, his mother and his sister) with a mild DM2 phenotype associated with a short (CCTG)100 expansion as far as regards the proband and his mother, while his sister shows larger expansion correlated to a more severe phenotype. FISH analysis with (CAGG)5 probe demonstrated that nuclear foci of mutant RNA were present in the proband muscle and co-localized with muscleblind-like proteins, determining their sequestration in the nucleus. This is one of the smallest expansion reported and the shortest with the evidence of nuclear foci. These data contribute to the clinical and molecular correlation of ZNF9 gene short expansion

Bottom Production

We review the prospects for bottom production physics at the LHC.Comment: 74 pages, Latex, 71 figures, to appear in the Report of the ``1999 CERN Workshop on SM physics (and more) at the LHC'', P. Nason, G. Ridolfi, O. Schneider G.F. Tartarelli, P. Vikas (conveners

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems

Performance of the CMS Level-1 trigger in proton-proton collisions at √s = 13 TeV

At the start of Run 2 in 2015, the LHC delivered proton-proton collisions at a center-of-mass energy of 13\TeV. During Run 2 (years 2015–2018) the LHC eventually reached a luminosity of 2.1× 10$^{34}$ cm$^{-2}$s$^{-1}$, almost three times that reached during Run 1 (2009–2013) and a factor of two larger than the LHC design value, leading to events with up to a mean of about 50 simultaneous inelastic proton-proton collisions per bunch crossing (pileup). The CMS Level-1 trigger was upgraded prior to 2016 to improve the selection of physics events in the challenging conditions posed by the second run of the LHC. This paper describes the performance of the CMS Level-1 trigger upgrade during the data taking period of 2016–2018. The upgraded trigger implements pattern recognition and boosted decision tree regression techniques for muon reconstruction, includes pileup subtraction for jets and energy sums, and incorporates pileup-dependent isolation requirements for electrons and tau leptons. In addition, the new trigger calculates high-level quantities such as the invariant mass of pairs of reconstructed particles. The upgrade reduces the trigger rate from background processes and improves the trigger efficiency for a wide variety of physics signals

Studio di sottopopolazioni cellulari staminali neuronali nello sviluppo di una terapia cellulomediata per le malattie del motoneurone

Neural stem cell subpopulations for cell-mediated therapy of motor neuron diseases Stem cell transplantation is a potential therapeutic strategy for motor neurons disease such as Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA) not only via cell replacement, but also by modification of the extracellular motor neuronal environment, through a trophic and neuroprotective effect, as well as immunomodulation strategies. We investigated the potential of a spinal cord neural stem cell population isolated on the basis of aldehyde dehydrogenase (ALDH) activity or double positive for Lewis X and the chemokine receptor CXCR4 (LeX+CXCR4+) to modify disease progression of nmd mice, an animal model of SMARD1 and SOD1-G93A mice, and animal model of ALS. In vitro, after exposure to morphogenetic stimuli these cells generate cholinergic motor neuron-like cells upon differentiation. ALDH(hi)SSC(lo) and LeX+CXCR4+ stem cells when transplanted in nmd and SOD1G93A mice generate motor neurons properly localized in the spinal cord ventral horns. Transplanted animals presented delayed disease progression, sparing of motor neurons and ventral root axons and increased lifespan. Our results support the therapeutic potential of Neural Stem Cell fractions through both neurogenesis and growth factors release in motor neuron disorders

Addressing Cell Therapy for Spinal Muscular Atrophy: Open Issues and Future Perspectives

Spinal muscular atrophy (SMA) is a devastating neuromuscular disease that affects children and young adults. The degeneration of spinal motor neurons, which are primarily involved in this disease, results in progressive muscular weakness and atrophy. As of 2016, there is no effective clinical treatment available for SMA patients, even if a large number of therapeutic approaches are being tested worldwide.Stem cells have been considered as a potential therapeutic strategy due to their plasticity and ability to direct differentiation in response to extracellular signals. Current cell-based therapies employ multiple types of stem cells to modify disease pathophysiology. This is theoretically achieved by either supporting neurons and glial cells through the release of neurotrophic factors, or directly replacing them.This chapter focuses on the therapeutic potential of different subtypes of human pluripotent stem cells and their derived phenotypes for SMA. This chapter also briefly describes their contribution in disease pathogenesis understanding. Finally, the chapter discusses the main challenges to overcome for stem cell therapeutic clinical translation

Somatic stem cell research for neural repair : current evidence and emerging perspectives

Recent evidence supports the existence of adult mammalian stem cell subpopulations, particularly within the bone marrow, that may be able to "transdifferentiate" across tissue lineage boundaries, thus offering an accessible source for therapeutic applications even for neural tissue repair. However, the difficulties in reproducing some experimental data, the rarity of the transdifferentiation events and observations that cell fusion may be an alternative explanation argue against the idea of stem cell plasticity. Investigations going beyond descriptive experiments and more mechanicistic approaches may provide a more solid foundation to adult stem cell therapeutic potential