34 research outputs found
HOX Genes Family and Cancer: A Novel Role for Homeobox B9 in the Resistance to Anti-Angiogenic Therapies
No full textSimple SummaryThe inhibition of angiogenesis, relying on the use of drugs targeting the VEGF signaling pathway, has become one of the main strategies for cancer treatment. However, the intrinsic and acquired resistance to this type of therapy limit its efficacy. Thus, the identification of novel therapeutic targets is urgently needed. The resistance to anti-angiogenic treatment often occurs through the activation of alternative VEGF independent signaling pathways and recruitment of bone marrow-derived pro-angiogenic cells in the tumor microenvironment. HOX genes are key regulators of embryonic development, also involved in angiogenesis and in cancer progression. HOXB9 upregulation occurs in many types of cancer and it has been identified as a critical transcription factor involved in tumour resistance to anti-angiogenic drugs. Indeed, HOXB9 modulates the expression of alternative pro-angiogenic secreted factors in the tumour microenvironment leading tumor escape from the anti-angiogenic treatments. Hence, HOXB9 could serves as a novel therapeutic target to overcome the resistance to anti-angiogenic therapies.Angiogenesis is one of the hallmarks of cancer, and the inhibition of pro-angiogenic factors and or their receptors has become a primary strategy for cancer therapy. However, despite promising results in preclinical studies, the majority of patients either do not respond to these treatments or, after an initial period of response, they develop resistance to anti-angiogenic agents. Thus, the identification of a novel therapeutic target is urgently needed. Multiple mechanisms of resistance to anti-angiogenic therapy have been identified, including the upregulation of alternative angiogenic pathways and the recruitment of pro-angiogenic myeloid cells in the tumor microenvironment. Homeobox containing (HOX) genes are master regulators of embryonic development playing a pivotal role during both embryonic vasculogenesis and pathological angiogenesis in adults. The importance of HOX genes during cancer progression has been reported in many studies. In this review we will give a brief description of the HOX genes and their involvement in angiogenesis and cancer, with particular emphasis on HOXB9 as a possible novel target for anti-angiogenic therapy. HOXB9 upregulation has been reported in many types of cancers and it has been identified as a critical transcription factor involved in resistance to anti-angiogenic drugs
Spazio e temporalità nella cappella Contarelli in San Luigi dei Francesi a Roma.
No full textIl saggio affronta il tema della Cappella Contarelli in S. Luigi dei Francesi, nota per ospitare i teleri di Caravaggio sugli episodi della vita di S. Matteo. Partendo dalla lettura del testo architettonico con le trasformazioni intervenute nel tempo, dai dati di archivio, si è potuto avanzare una originale e nuova attribuzione dell'autore della architettura della Cappella Contarelli. L'architetto segue le indicazioni artistiche del pittore lomabardo, determinando un'opera esplicitamente intesa come strumento di esaltazione della formatività simbolica e luministica dell'opera di Caravaggio
The effects of a combined bodyweight-based and elastic bands resistance training, with or without protein supplementation, on muscle mass, signaling and heat shock response in healthy older people
No full textThis investigation sought to determine the effects of twelve weeks of resistance exercise training in addition to protein supplementation on body composition, markers of muscle atrophy/hypertrophy and heat shock response (HSR) in healthy older adults. Thirty-eight healthy sedentary participants (M/F, 18/20; age, 63.5 ± 4.4 y) were randomly assigned to four groups: I) PLACEBO: no training, receiving placebo sachets; II) NUTRITION: no training, receiving protein supplementation sachets; III) EXERCISE PLACEBO: training, placebo sachets and IV) EXERCISE NUTRITION: training, receiving protein sachets. The resistance training (using bodyweight and elastic bands) consisted of 45 min supervised training sessions, 3×/week. Participants from both exercise groups increased their total lean body mass (from 48.4 ± 8.7 to 49.2 ± 8.7 kg and from 44.9 ± 7.8 to 45.9 ± 8.1 kg, average of gain ~0.8 and 1 kg, placebo and nutrition respectively) and improved results in physical tests. Exercise nutrition group also reduced their body fat (from 34.8 ± 7.3 to 32.9 ± 7.4%), increased the expression of proteins/gene involved on the HSR, S6 and eEF2, while FOXO3 and Murf1 were reduced. Expression of MHC-I was reduced in both exercise groups while MHC-IIa increased, with no effect of protein supplementation alone. Body-weight and elastic bands based resistance exercise prompted, in healthy older people, improvements in body composition and muscle function. When protein supplementation was added to the people engaged in resistance training, improvements in fat mass and changes in skeletal muscle signaling were detected, favoring protein synthesis pathways and the protective heat shock response
Effect of hyaluronic acid local injections on Achilles tendinitis: an observational study on tendon viscoelastic properties in recreational runners
No full textPurpose: Achilles tendinitis (AT) causes 5% of professional athletes
to end their careers; in Europe AT affects ca. 10 millions recreational
runners. The aim of this study was to evaluate the clinical and
functional efficacy of a three-local injections regimen of hyaluronic
acid (HA) in ameliorating pain score and function in middle aged
recreational runners with AT, whose functional and clinical param-
eters were recorded integrating multiple techniques.
Methods: 8 recreational runners previously diagnosed for monolat-
eral AT were enrolled. AT was confirmed before the first local HA
injection (T0) by clinical examination, MRI and thermography. At T0
patients were assessed for maximal voluntary isometric contraction
(MVI) involving Achilles tendon (both injured and healthy), and pain
level with a Likert scale; Achilles tendon viscoelastic state, i.e. tone
and stiffness, were then measured at relaxed state and at 10% of MVI
with MyotonPro (Myoton Ltd, UK). Finally patients received the first
HA injection (RegenFlex T&M, a blend of 2–1000 kDa HA,
Regenyal, IT). All the measurements were repeated at T1 (15 days
after the first injections and immediately prior the second), at T2
(15 days after the second injection and prior the third) and at T3
(15 days after the third injection), i.e. over a total of 45 days in which
clinical visits were also performed. Furthermore, before each injec-
tion, injured tendon exudates were collected by needle aspiration.
Results: At T0, tone and stiffness values were significantly different
between injured and contralateral tendons, especially when measured
at the relaxed state. Pain score and MVI, coherently with clinical
outcomes, were significantly higher and lower in injured tendons,
respectively. Interestingly, the above differences gradually disap-
peared at T1, 2 and 3. In keeping with these results, tendon exudates
volumes also decreased
News on Prester John in the Rome of Gregory XIII: Echoes of the Ethiopian Question in the Contarelli Chapel from Muziano to Caravaggio
No full textThe essay examines the contents of the Relatione della Religione, & Stato del Re
d’Ethiopia, detto «Prete Gianni» addressed to Pope Gregory XIII, dwelling on some news
related to the relationship of Ethiopian Christians with sacred images and on the echoes
of Ethiopian religiosity and the problematic dialogue between Catholicism and Abyssini an Christianity traceable in some artistic commissions of the second Roman 16th century.
The article intends to open to new possible interpretations of the iconographic program
of the Contarelli Chapel in S. Luigi dei Francesi, whose decoration, planned as early as
1565 by the apostolic referendario Mathieu Cointrel, made cardinal by Pope Boncom pagni in 1583, was only completed between 1599 and 1602 by Caravaggi
Targeting KRAS: The Elephant in the Room of Epithelial Cancers
No full textMutations of the proto-oncogene KRAS are the most frequent gain-of-function alterations found in cancer. KRAS is mutated in about 30% of all human tumors, but it could reach more than 90% in certain cancer types such as pancreatic adenocarcinoma. Although historically considered to be undruggable, a particular KRAS mutation, the G12C variant, has recently emerged as an actionable alteration especially in non-small cell lung cancer (NSCLC). KRAS(G12C) and pan-KRAS inhibitors are being tested in clinical trials and have recently shown promising activity. Due to the difficulties in direct targeting of KRAS, other approaches are being explored. The inhibition of target upstream activators or downstream effectors of KRAS pathway has shown to be moderately effective given the evidence of emerging mechanisms of resistance. Various synthetic lethal partners of KRAS have recently being identified and the inhibition of some of those might prove to be successful in the future. The study of escape mechanisms to KRAS inhibition could support the utility of combination strategies in overcoming intrinsic and adaptive resistance and enhancing clinical benefit of KRAS(G12C) inhibitors. Considering the role of the microenvironment in influencing tumor initiation and promotion, the immune tumor niche of KRAS mutant tumors has been deeply explored and characterized for its unique immunosuppressive skewing. However, a number of aspects remains to be fully understood, and modulating this tumor niche might revert the immunoresistance of KRAS mutant tumors. Synergistic associations of KRAS(G12C) and immune checkpoint inhibitors are being tested
Effects of acute aerobic, resistance and combined exercises on 24-h glucose variability and skeletal muscle signalling responses in type 1 diabetics
No full textPurpose: To compare the effect of high-intensity aerobic (AER), resistance (RES), and combined (COMB: RES + AER) exercise, on interstitial glucose (IG) variability and skeletal muscle signalling pathways in type 1 diabetes (T1D). Methods: T1D participants (6 M/6F) wore a flash glucose monitoring system in four randomized sessions: one control (CONT), and one AER, RES and COMB (40 min each). Mean amplitude of glycemic excursions (MAGE), standard deviation (SD) and coefficient variation (CV) of IG were used to compare the 24 h post-exercise IG variability. Blood and muscle samples were collected to compare exercise-induced systemic and muscle signalling responses related to metabolic, growth and inflammatory adaptations. Results: Both RES and COMB decreased the 24 h MAGE compared to CONT; additionally, COMB decreased the 24 h SD and CV. In the 6–12 h post-exercise, all exercise modalities reduced the IG CV while SD decreased only after COMB. Both AER and COMB stimulated the PGC-1α mRNA expression and promoted the splicing of IGF-1Ea variant, while Akt and p38MAPK phosphorylation increased only after RES and COMB. Additionally, COMB enhanced eEF2 activation and RES increased myogenin and MRF4 mRNA expression. Blood lactate and glycerol levels and muscle IL-6, TNF-α, and MCP-1 mRNAs increased after all exercise sessions, while serum CK and LDH level did not change. Conclusion: COMB is more effective in reducing IG fluctuations compared to single-mode AER or RES exercise. Moreover, COMB simultaneously activates muscle signalling pathways involved in substrate metabolism and anabolic adaptations, which can help to improve glycaemic control and maintain muscle health in T1D
Antimicrobial resistance profile of atypical Enteropathogenic Escherichia coli strains.
No full textA Escherichia coli enteropatogênica atípica (aEPEC) é um dos principais agentes causadores de diarreia infantil e às vezes é necessário o tratamento com antimicrobianos. O objetivo do presente trabalho foi verificar o perfil de resistência aos antimicrobianos de 72 amostras de aEPEC, correlacionando com o perfil genético de resistência e a produção de β-lactamases de espectro extendido (ESBL). As aEPEC apresentaram resistência aos β-lactamâmicos, sulfonamidas, tetraciclinas, aminoglicosídeos e ansamicina, verificadas através de disco difusão. Multirresistência foi identificada em 27,8%. Treze amostras (18,1%) produziram ESBL. Os genes de resistência encontrados através de PCR foram: sul1 - 50%, sul2 - 86,4%, tetA - 42,1%, tetB - 68,4%, tetC- 5,3%, blaCTX-M - 26,1%, blaTEM -78,3%, blaSHV - 4,4% e intl - 35,7%. O conhecimento sobre o perfil de resistência e produção de ESBLs é muito importante na orientação do tratamento adequado quando se fizer necessário, além de conhecer o potencial de resistência que poderiam vir a ser transferidos para outras bactérias.The atypical Enteropathogenic Escherichia coli (aEPEC) is one of the most common childhood diarrhea`s agent, and sometimes the antimicrobials treatment may be necessary. The aim of this study was verify the antimicrobial resistance profile of 72 aEPEC strains, correlating with the resistance genetic profile, and the extended-spectrum β-lactamases (ESBL) production. The aEPEC strains presented resistance to β-lactams, Sulfonamides, Tetracycline, Aminoglycoside, and Ansamycin, verified through disc diffusion. Multiresistance was identified in 27.8%. Thirteen strains (18.1%) produced ESBL. The resistance genes found through PCR were: sul1 - 50%, sul2 86.4%, tetA 42.1%, tetB 68.4%, tetC- 5.3%, blaCTX-M 26.1%, blaTEM -78.3%, blaSHV 4.4%, and intl 35.7%. The knowledge about resistance profile´s and ESBL production is very important in guiding the most appropriate treatment when it is necessary, in addition to knowing the resistance potential that could be transferred to other bacteria
MIR retroposon exonization promotes evolutionary variability and generates species-specific expression of IGF-1 splice variants
No full textInsulin-like growth factor (IGF) -1 is a pleiotropic hormone exerting mitogenic and anti-apoptotic effects. Inclusion or exclusion of exon 5 into the IGF-1 mRNA gives rise to three transcripts, IGF-1Ea, IGF-1Eb and IGF-1Ec, which yield three different C-terminal extensions called Ea, Eb and Ec peptides. The biological signifi- cance of the IGF-1 splice variants and how the E-peptides affect the actions of mature IGF-1 are largely unknown. In this study we investigated the origin and conservation of the IGF-1 E-peptides and we compared the pattern of expression of the IGF-1 isoforms in vivo, in nine mammalian species, and in vitro using human and mouse IGF-1 minigenes.
Our analysis showed that only IGF-1Ea is conserved among all vertebrates, whereas IGF-1Eb and IGF-1Ec are an evolutionary novelty originated from the exonization of a mammalian interspersed repetitive-b (MIR-b) element. Both IGF-1Eb and IGF-1Ec mRNAs were constitutively expressed in all mammalian species analyzed but their expression ratio varies greatly among species. Using IGF-1 minigenes we demonstrated that divergence in cis-acting regulatory elements between human and mouse conferred species-specific features to the exon 5 region. Finally, the protein-coding sequences of exon 5 showed low rate of synonymous mutations and contain disorder-promoting amino acids, suggesting a regulatory role for these domains.
In conclusion, exonization of a MIR-b element in the IGF-1 gene determined gain of exon 5 during mammalian evolution. Alternative splicing of this novel exon added new regulatory elements at the mRNA and protein level potentially able to regulate the mature IGF-1 across tissues and species
