The persistent dynamic secrets of senescence

While the beneficial versus detrimental implications of the senescence-associated secretome remain an issue of debate, time-resolved analyses of its composition, regulatory mechanisms and functional consequences have been largely missing. The dynamic activity of NOTCH is now shown to direct two distinct senescence phenotypes, by first promoting a pro-senescent TGF-{beta}1-dependent secretome, followed by a second wave of pro-inflammatory, senescence-clearing cytokines

DNp73 improves generation efficiency of human induced pluripotent stem cells

<p>Abstract</p> <p>Background</p> <p>Recent studies have found that p53 and its' associated cell cycle pathways are major inhibitors of human induced pluripotent stem (iPS) cell generation. In the same family as p53 is p73, which shares sequence similarities with p53. However, p73 also has distinct properties of its own, such as two alternative promoters to express transactivation of p73 (TAp73) and N terminal deleted p73 (DNp73). Functionally, TAp73 acts similarly to p53 in tumor suppression. However, DNp73, on the other hand acts as an oncogene to suppress p53 and p73 induced apoptosis. Therefore, how can p73 have opposing roles in human iPS cell generation?</p> <p>Results</p> <p>Transcription factors, Oct4, Sox2, Klf4 and cMyc (4TF, Yamanaka factors) are used as basal conditions to generate iPS cells. In addition, the factor of DNp73(actually alpha splicing DNp73, DNp73α) is used to generate iPS cells. The experiment found that the addition of DNp73 gene increases human iPS cell generation efficiency by 12.6 folds in comparison to human fibroblast cells transduced with only the basal conditions. Also, iPS cells generated with DNp73 expression are more resistant to <it>in vitro </it>and <it>in vivo </it>differentiation.</p> <p>Conclusions</p> <p>This study found DNp73, a family member of p53, is also involved in the human iPS cell generation. Specifically, that the involvement of DNp73 generates iPS cells that are more resistant to <it>in vitro </it>and <it>in vivo </it>differentiation. Therefore, this data may prove to be useful in future developmental studies and cancer researches.</p

Paracrine cellular senescence exacerbates biliary injury and impairs regeneration

Senescence has been suggested as causing biliary cholangiopathies but how this is regulated is unclear. Here, the authors generate a mouse model of biliary senescence by deleting Mdm2 in bile ducts and show that inhibiting TGFβ limits senescence-dependent aggravation of cholangiopathies

Effect of eplerenone on extracellular cardiac matrix biomarkers in patients with acute ST-elevation myocardial infarction without heart failure: insights from the randomized double-blind REMINDER Study

Objective: Aldosterone stimulates cardiac collagen synthesis. Circulating biomarkers of collagen turnover provide a useful tool for the assessment of cardiac remodeling in patients with an acute myocardial infarction (MI).  Methods: The REMINDER trial assessed the effect of eplerenone in patients with an acute ST-elevation Myocardial Infarction (STEMI) without known heart failure (HF), when initiated within 24 h of symptom onset. The primary outcome was almost totally (>90%) driven by natriuretic peptide (NP) thresholds after 1-month post-MI (it also included a composite of cardiovascular death or re-hospitalization or new onset HF or sustained ventricular tachycardia or fibrillation or LVEF ≤40% after 1-month post-MI). This secondary analysis aims to assess the extracellular matrix marker (ECMM) levels with regards to: (1) patients` characteristics; (2) determinants; (3) and eplerenone effect.  Results: Serum levels of ECMM were measured in 526 (52%) of the 1012 patients enrolled in the REMINDER trial. Patients with procollagen type III N-terminal propeptide (PIIINP) above the median were older and had worse renal function (p < 0.05). Worse renal function was associated with increased levels of PIIINP (standardized β ≈ 0.20, p < 0.05). Eplerenone reduced PIIINP when the levels of this biomarker were above the median of 3.9 ng/mL (0.13 ± 1.48 vs. -0.37 ± 1.56 ng/mL, p = 0.008). Higher levels of PIIINP were independently associated with higher proportion of NP above the prespecified thresholds (HR = 1.95, 95% CI 1.16-3.29, p = 0.012).  Conclusions: Eplerenone effectively reduces PIIINP levels when baseline values were above the median. Eplerenone may limit ECMM formation in post-MI without HF

A Senescence-Like Cell-Cycle Arrest Occurs During Megakaryocytic Maturation: Implications for Physiological and Pathological Megakaryocytic Proliferation

During normal megakaryocyte development, in response to thrombopoetin, mature cells enter a senescence-like state in which they shed platelets; this state, characterized by cell cycle arrest, is defective in malignant megakaryocytes

Senescent cells evade immune clearance via HLA-E-mediated NK and CD8(+) T cell inhibition

Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8 + T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing

Chronic panсreatitis as a mask of periodical disease

В связи с высоким уровнем миграционных процессов в современном мире, не стоит предавать основное значение этническому (армяне, евреи) или географическому (Средиземноморье) факторам при постановке диагноза периодической болезни. Приведенный клинический пример показывает возможности диагностики ПБ основанный, в первую очередь, на тщательном анализе клинической картины и анамнеза заболевания. Несмотря на редкость встречаемости этого заболевания, о нем необходимо помнить не только семейным врачам и врачам-ревматологам, но и хирургам, чтобы оградить пациента от множественных необоснованных хирургических вмешательств. В нашем случае, правильный диагноз пациенту не был установлен в течении 13 лет, своевременная его постановка, позволила бы лишить его многолетних страданий и вовремя начать патогенетическое лечение, что в свою очередь разрешило бы снизить риск развития дальнейших осложнений заболевания.У зв’язку з високим рівнем міграційних процесів у сучасному світі, не варто надавати основне значення етнічному (вірмени, євреї) або географічному (Середземномор’я) факторам під час встановлення діагнозу періодичної хвороби. Наведений клінічний приклад показує можливість діагностики ПХ, що ґрунтується, в першу чергу, на ретельному аналізі клінічної картини і анамнезу захворювання. Незважаючи на рідкість зустрічальності цього захворювання, про нього необхідно пам’ятати не тільки сімейним лікарям і лікарямревматологам, але й хірургам, щоб відгородити пацієнта від багаточисленних необґрунтованих хірургічних втручань. В нашому випадку, правильний діагноз пацієнту не був встановлений на протязі 13 років, сучасне його встановлення, дозволило б позбавити його від багаторічних страждань і своєчасно почати патогенетичне лікування, що в свою чергу дозволило б знизити ризик розвитку подальших ускладнень захворювань.Present time neither ethnical nor geographical factor has a key role in the diagnosis of periodical disease. The investigation done shows that the pathology under study may be determined after a careful analysis of clinical symptoms and detailed study of the patient’s life history. While the pathology under discussion is a rather rare one family doctors, reumatologists and especially surgeons should remember about it with the aim to protect a patient from reasonless intervention