Catholic University of the Sacred Heart

About: Catholic University of the Sacred Heart is a education organization based out in Milan, Lombardia, Italy. It is known for research contribution in the topics: Population & Medicine. The organization has 13592 authors who have published 31048 publications receiving 853961 citations.

Cancer Stem Cell Analysis and Clinical Outcome in Patients with Glioblastoma Multiforme

Abstract: Purpose: Cancer stem cells (CSC) are thought to represent the population of tumorigenic cells responsible for tumor development. The stem cell antigen CD133 identifies such a tumorigenic population in a subset of glioblastoma patients. We conducted a prospective study to explore the prognostic potential of CSC analysis in glioblastoma patients. Experimental Design: We investigated the relationship between the in vitro growth potential of glioblastoma CSCs and patient death or disease progression in tumors of 44 consecutive glioblastoma patients treated with complete or partial tumorectomy followed by radiotherapy combined with temozolomide treatment. Moreover, we evaluated by immunohistochemistry and immunofluorescence the prognostic value of the relative presence of CD133 + and CD133 + /Ki67 + cells in patient tumors. Results: In vitro CSC generation and the presence of ≥2% CD133 + cells in tumor lesions negatively correlated with overall ( P = 0.0001 and 0.02, respectively) and progression-free ( P = 0.0002 and 0.01, respectively) survival of patients. A very poor overall ( P = 0.007) and progression-free ( P = 0.001) survival was observed among patients whose tumors contained CD133 + cells expressing Ki67. Taking into account symptom duration, surgery type, age, O 6 -methylguanine-DNA methyltransferase promoter methylation, and p53 status, generation of CSCs and CD133/Ki67 coexpression emerged as highly significant independent prognostic factors, with an adjusted hazard ratio of 2.92 (95% confidence interval, 1.37-6.2; P = 0.005) and 4.48 (95% confidence interval, 1.68-11.9; P = 0.003), respectively. Conclusions: The analysis of CSCs may predict the survival of glioblastoma patients. In vitro CSC generation and presence of CD133 + /Ki67 + cells are two considerable prognostic factors of disease progression and poor clinical outcome.

Sarcopenia: A Time for Action. An SCWD Position Paper.

Abstract: The term sarcopenia was introduced in 1988. The original definition was a "muscle loss" of the appendicular muscle mass in the older people as measured by dual energy x-ray absorptiometry (DXA). In 2010, the definition was altered to be low muscle mass together with low muscle function and this was agreed upon as reported in a number of consensus papers. The Society of Sarcopenia, Cachexia and Wasting Disorders supports the recommendations of more recent consensus conferences, i.e. that rapid screening, such as with the SARC-F questionnaire, should be utilized with a formal diagnosis being made by measuring grip strength or chair stand together with DXA estimation of appendicular muscle mass (indexed for height2). Assessments of the utility of ultrasound and creatine dilution techniques are ongoing. Use of ultrasound may not be easily reproducible. Primary sarcopenia is aging associated (mediated) loss of muscle mass. Secondary sarcopenia (or disease-related sarcopenia) has predominantly focused on loss of muscle mass without the emphasis on muscle function. Diseases that can cause muscle wasting (i.e. secondary sarcopenia) include malignant cancer, COPD, heart failure, and renal failure and others. Management of sarcopenia should consist of resistance exercise in combination with a protein intake of 1 to 1.5 g/kg/day. There is insufficient evidence that vitamin D and anabolic steroids are beneficial. These recommendations apply to both primary (age-related) sarcopenia and secondary (disease related) sarcopenia. Secondary sarcopenia also needs appropriate treatment of the underlying disease. It is important that primary care health professionals become aware of and make the diagnosis of age-related and disease-related sarcopenia. It is important to address the risk factors for sarcopenia, particularly low physical activity and sedentary behavior in the general population, using a life-long approach. There is a need for more clinical research into the appropriate measurement for muscle mass and the management of sarcopenia. Accordingly, this position statement provides recommendations on the management of sarcopenia and how to progress the knowledge and recognition of sarcopenia.

Sarcopenia and Physical Frailty: Two Sides of the Same Coin

Abstract: Since the last decade, geriatrics and geron-tology researchers have been devoting anincreasing amount of efforts in the attemptof designing, developing, and implement-ing preventive interventions against con-ditions determining/driving the disablingcascade. The urgency of moving ahead inthe field is not merely dictated by scientificinterests; such need has indeed become afrequent and central item in the agendas ofpublic health authorities (Guralnik et al.,1996). In fact, there is a growing demandfor the identification of effective solutionsagainst the detrimental consequences thatage-related conditions (in particular, dis-abilities) exert on our healthcare systems.Specialattentionhasbeengiventosarcope-nia (Janssen et al., 2004) and frailty (Clegget al., 2013) because both are (1) highlyprevalent in the elderly, (2) associated withnegative health-related events, (3) poten-tially reversible, and (4) relatively easy toimplement in the clinical practice.The term “sarcopenia” was coined byRosenberg to indicate the loss of musclemass that accompanies aging. He clearlystated that “there is probably no decline instructureandfunctionmoredramaticthanthe decline in lean body mass or musclemass over the decades of life” (Rosenberg,1997). The muscle loss was therefore seenasameansof convenienceforexploringtheaging process and its consequences on anindividual’s health. Nevertheless, the skele-talmusclecannotbeisolatedbythehostingorganism. As such, it is still subject to theinfluence of all the positive and negativestressors to which the organism is exposed.In other words,the endogenous and exoge-nous phenomena capable of modifying theaging trajectory of the organism can also(more or less directly) influence the qualityand quantity of the muscle.Frailtyisthetermusedtoindicateageri-atric syndrome characterized by reducedhomeostatic reserves, which exposes theindividual at increased risk of negativehealth-related events (including falls, hos-pitalizations, worsening disability, institu-tionalization, and mortality) (Rodriguez-Manas et al., 2012; Clegg et al., 2013).Different operational definitions have beenproposed for capturing the frailty status,each one focusing on specific aspects of thesyndrome and detecting slightly differentrisk profiles (Theou et al., 2014). Never-theless, there is an overall agreement aboutthe key role that physical function (in par-ticular, mobility) plays in the determina-tion of the status of extreme vulnerability(Ferrucci et al., 2004; Daniels et al., 2008;Abellan van Kan et al., 2009).Since the beginning (roughly about 15–20years ago), sarcopenia and frailty havebeen studied in parallel. Being organ-specific, sarcopenia was more frequentlyobject of research in basic science, whereasthe concept of frailty tended to be moreeasily applied in the clinical setting (Bauerand Sieber, 2008). However, it was quiteinevitable that the two would have sooneror later started converging due to theirclose relationship with the aging process.Unfortunately, the definition of a clearframework within which sarcopenia andfrailty can be accommodated and stud-ied has yet to come. One major issue inthis context is the long-lasting, tiring, andpotentially pointless controversy about thecausal relationship existing between thetwo. Determining whether frailty is dueto sarcopenia, or sarcopenia is a clinicalmanifestation of frailty is consuming con-siderable efforts,and (from a very practicalviewpoint) rather resembles the problemof “the egg and the chicken.”We realize that the clarification of thispoint might have major consequences inthe field,determining different risk profilesto be detected and, consequently, redraw-ing outcomes as well as interventions to beadopted.Yet,theisolationof asinglepatho-physiological determinant responsible forthesecomplexconditions(aswellasforanyother age-related process) is quite unlikelyto be obtained, simply because aging isa complicated and still largely unknownphenomenon (Cesari et al., 2013).By stating this, we are not surrenderingto the current limitations of science. Weare instead soliciting the taking of morepragmatic decisions on this topic, waitingthat next-to-come scientific advancementsallow a better clarification and definitionof such urgent and pivotal matters. Fromthis perspective, deconstructing the innerfoundations of these“twin”conditions andtrying to focus on the shared and clinicalrelevant features of them might representa possible solution. By this way, we mighthave the opportunity to (1) define a uniquetarget for both sarcopenia and frailty, (2)simplify their operational definition, and(3)promotetheimplementationof thetwoconditions in both clinical and researchsettings.As shown in

p63 Gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation

Abstract: p63 mutations have been associated with EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate), as well as with nonsyndromic split hand–split foot malformation (SHFM). We performed p63 mutation analysis in a sample of 43 individuals and families affected with EEC syndrome, in 35 individuals affected with SHFM, and in three families with the EEC-like condition limb-mammary syndrome (LMS), which is characterized by ectrodactyly, cleft palate, and mammary-gland abnormalities. The results differed for these three conditions. p63 gene mutations were detected in almost all (40/43) individuals affected with EEC syndrome. Apart from a frameshift mutation in exon 13, all other EEC mutations were missense, predominantly involving codons 204, 227, 279, 280, and 304. In contrast, p63 mutations were detected in only a small proportion (4/35) of patients with isolated SHFM. p63 mutations in SHFM included three novel mutations: a missense mutation (K193E), a nonsense mutation (Q634X), and a mutation in the 3′ splice site for exon 5. The fourth SHFM mutation (R280H) in this series was also found in a patient with classical EEC syndrome, suggesting partial overlap between the EEC and SHFM mutational spectra. The original family with LMS (van Bokhoven et al. 1999) had no detectable p63 mutation, although it clearly localizes to the p63 locus in 3q27. In two other small kindreds affected with LMS, frameshift mutations were detected in exons 13 and 14, respectively. The combined data show that p63 is the major gene for EEC syndrome, and that it makes a modest contribution to SHFM. There appears to be a genotype-phenotype correlation, in that there is a specific pattern of missense mutations in EEC syndrome that are not generally found in SHFM or LMS.

Ataluren treatment of patients with nonsense mutation dystrophinopathy

Abstract: Introduction: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. Methods: Randomized, double-blind, placebo-controlled study; males ≥5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N = 57); ataluren 20, 20, 40 mg/kg (N = 60); or placebo (N = 57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. Results: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ = 31.3 meters, post hoc P = 0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. Conclusions: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need. Muscle Nerve 50: 477–487, 2014