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MicroRNAs (miRNAs) have been involved in the pathogenesis of different types of cancer; however, their function in pituitary tumorigenesis remains poorly understood. Cyclic-AMP-dependent protein kinase-defective pituitaries occasionally form aggressive growth-hormone (GH)-producing pituitary tumors in the background of hyperplasia caused by haploinsufficiency of the protein kinase’s main regulatory subunit, PRKAR1A . The molecular basis for this development remains unknown. We have identified a 17-miRNA signature of pituitary tumors formed in the background of hyperplasia (caused in half of the cases by PRKAR1A -mutations). We selected two miRNAs on the basis of their functional screen analysis: inhibition of miR-26b expression and upregulation of miR-128 suppressed the colony formation ability and invasiveness of pituitary tumor cells. Furthermore, we identified that miR-26b and miR-128 affected pituitary tumor cell behavior through regulation of their direct targets, PTEN and BMI1 , respectively. In addition, we found that miR-128 through BMI1 direct binding on the PTEN promoter affected PTEN expression levels and AKT activity in the pituitary tumor cells. Our in vivo data revealed that inhibition of miR-26b and overexpression of miR-128 could suppress pituitary GH3 tumor growth in xenografts. Taken together, we have identified a miRNA signature for GH-producing pituitary tumors and found that miR-26b and miR-128 regulate the activity of the PTEN–AKT pathway in these tumors. This is the first suggestion of the possible involvement of miRNAs regulating the PTEN–AKT pathway in GH-producing pituitary tumor formation in the context of hyperplasia or due to germline PRKAR1A defects. MiR-26b suppression and miR-128 upregulation could have therapeutic potential in GH-producing pituitary tumor patients.

The peroxisome proliferators-activated receptor ( PPAR) γ pathway is involved in cancer, but it appears to have both tumor suppressor and oncogenic functions. In neuroblastoma cells, miR-27b targets the 3′ untranslated region of PPAR γ and inhibits its mRNA and protein expression. miR-27b overexpression or PPAR γ inhibition blocks cell growth in vitro and tumor growth in mouse xenografts. PPAR γ activates expression of the pH regulator NHE1 , which is associated with tumor progression. Lastly, miR-27b through PPAR γ regulates nuclear factor-κB activity and transcription of inflammatory target genes. Thus, in neuroblastoma, miR-27b functions as a tumor suppressor by inhibiting the tumor-promoting function of PPAR γ, which triggers an increased inflammatory response. In contrast, in breast cancer cells, PPAR γ inhibits NHE1 expression and the inflammatory response, and it functions as a tumor suppressor. We suggest that the ability of PPAR γ to promote or suppress tumor formation is linked to cell type-specific differences in regulation of NHE1 and other target genes.

Objective:To investigate whether epigenetic mechanisms can regulate leptin’s expression and affect its downstream targets as metalloproteinases 3,9,13 in osteoarthritic chondrocytes.Methods:DNA methylation in leptin promoter was measured by DNA bisulfite sequencing, and mRNA expression levels were measured by real-time quantitative PCR in osteoarthritic as well as in normal cartilage. Osteoarthritic articular cartilage samples were obtained from two distinct locations of the knee (n = 15); from the main defective area of maximum load (advanced osteoarthritis (OA)) and from adjacent macroscopically intact regions (minimal OA). Using small interference RNA, we tested if leptin downregulation would affect matrix metalloproteinase (MMP)-13 activity. We also evaluated the effect of the demethylating agent, 5′-Aza-2-deoxycytidine (AZA) and of the histone deacetylase inhibitor trichostatin A (TSA) on leptin expression in chondrocyte cultures. Furthermore, we performed chromatin immunoprecipitation in leptin’s promoter area.Results:We found a correlation between leptin expression and DNA methylation and also that leptin controls MMP-13 activity in chondrocytes. Leptin’s downregulation with small interference RNA inhibited MMP-13 expression dramatically. After 5-AZA application in normal chondrocytes, leptin’s methylation was decreased, while its expression was upregulated, and MMP-13 was activated. Furthermore, TSA application in normal chondrocyte cultures increased leptin’s expression. Also, chromatin immunoprecipitation in leptin’s promoter after TSA treatment revealed that histone H3 lysines 9 and 14 were acetylated.Conclusion:We found that epigenetic mechanisms regulate leptin’s expression in chondrocytes affecting its downstream target MMP-13. Small interference RNA against leptin deactivated directly MMP-13, which was upregulated after leptin’s epigenetic reactivation, raising the issue of leptin’s therapeutic potential for osteoarthritis.

Osteoarthritis is a degenerative joint disease affecting middle-aged and elderly patients. It mainly involves weight-bearing joints such as the hip, knee and spine as well as the basilar joint of the thumb, causing dysfunction and painful symptoms. Often, joint arthritis is accompanied by cartilage defects, joint space narrowing, osteophytes, bone sclerosis and subchondral bone cysts (SBC). The aim of the present study was to explore the pathophysiology responsible for the development of SBCs as well as the association between SBCs and disease progress, the level of clinical symptoms and their impact on postoperative outcomes and risk of possible complications following joint replacements if left untreated. A literature review on PubMed articles was conducted to retrieve and evaluate all available evidence related to the main objective mentioned above. A few theories have been put forth to explain the formation process of SBCs. These involve MMPs secretion, angiogenesis, and enhanced bone turnover as a biological response to abnormal mechanical loads causing repeated injuries on cartilage and subchondral tissue during the development of arthritis. However, the application of novel therapeutics, celecoxib-coated microspheres, local administration of IGF-1 and activated chondrocytes following surgical debridement of SBCs hinders the expansion of SBCs and prevents the progression of osteoarthritis.

In the present study we analyzed the regulation of the two isoforms of the RhoA-specific guanine nucleotide exchange factor Net1 by transforming growth factor-β (TGF-β) in keratinocytes. We report that short-term TGF-β treatment selectively induced Net1 isoform2 (Net1A) but not Net1 isoform1. This led to upregulation of cytoplasmic Net1A protein levels that were necessary for TGF-β-mediated RhoA activation. Smad signaling and the MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway were involved in Net1A upregulation by TGF-β. Interestingly, long-term TGF-β treatment resulted in Net1 mRNA downregulation and Net1A protein degradation by the proteasome. Furthermore, we identified the microRNA miR-24 as a novel post-transcriptional regulator of Net1A expression. Silencing of Net1A resulted in disruption of E-cadherin- and zonula occludens-1 (ZO-1)-mediated junctions, as well as expression of the transcriptional repressor of E-cadherin, Slug and the mesenchymal markers N-cadherin, plasminogen activator inhibitor-1 (PAI-1) and fibronectin, indicating that late TGF-β-induced downregulation of Net1A is involved in epithelial-to-mesenchymal transition (EMT). Finally, miR-24 was found to be implicated in the regulation of the EMT program in response to TGF-β and was shown to be directly involved in the TGF-β-induced breast cancer cell invasiveness through Net1A regulation. Our results emphasize the importance of Net1 isoform2 in the short- and long-term TGF-β-mediated regulation of EMT.

Vasopressin has been used to augment blood pressure; however, cardiovascular effects after cardiac surgery have not been well established. The primary objective of this study was to survey the current literature and quantify the pooled effect of vasopressin on hemodynamic parameters in children after pediatric cardiac surgery. A systematic review was conducted to identify studies characterizing the hemodynamic effects of vasopressin after pediatric cardiac surgery. Studies were assessed and those of satisfactory quality with pre- and post-vasopressin hemodynamics for each patient were included in the final analyses. 6 studies with 160 patients were included for endpoints during the first 2 h of infusions. Patients who received vasopressin infusion had greater mean, systolic, and diastolic blood pressures and lower heart rates at 2 h after initiation. 8 studies with 338 patients were included for the effects at 24 h. Patients who received vasopressin infusion had lower central venous pressures and decreased lactate concentrations 24 h after initiation. A subset analysis for children with functionally univentricular hearts found significant decrease in inotrope score and central venous pressure. A subset analysis for neonates found significant decrease in inotrope score and fluid balance. Vasopressin leads to decrease in heart rate and increase in blood pressure in the first 2 h of initiation. Later effects include decrease in inotrope score, central venous pressure, fluid balance, and in lactate within the first 24 h. Findings vary in neonates and in those with functionally univentricular hearts although beneficial effects are noted in both.

Background Osteoarthritis (ΟΑ) is characterized by cartilage breakdown and subchondral sclerosis. Micro‐fractures of the calcified tissues have been, also, detected, but their exact role has not been elucidated yet. This study was to examine the frequency of cracks during OA progression and to correlate them with the underlying cellular modifications and matrix metalloproteinase‐2 (MMP‐2) expression using histological/immunohistological methods. Methods Overall, 20 patients and 3 controls (9 specimens per patient), aged 60–89 years, diagnosed with hip/knee OA were included. The development of cracks was examined in 138 sections, whereas the expression of MMP‐2 was examined in 69 additional sections. Results Based on Mankin score, three groups of OA severity were analyzed: Group I (mild) was constituted of sections with score 1–5 while Groups II (moderate) and III (severe) with score 6–7 and greater or equal to 8, respectively. Demographic characteristics did not reveal any association between the number of microdefects and age or body mass index (BMI). Cartilage micro‐cracks were increased during moderate and severe OA, while bone cracks were increased during mild and severe OA. In knee OA, cartilage cracks were not correlated with Mankin score, whereas in hip OA they appeared association with severity score. Bone cracks were positively correlated with matrix apoptotic osteocytes and osteoblastic cells, but not with osteoclasts. MMP‐2 immunostaining was increasing by OA severity in the osteochondral unit. Similarly, MMP‐2 was expressed on the microcracks’ wall mainly in Group III. Conclusion Our data displayed that bone cracks during primary OA stages, represent an early adaptative mechanism aiming to maintain cartilage integrity. Accumulation of bone defects and concomitant increase of apoptotic osteocytes activated an abnormal remodeling due to osteoblastic activity, in which MMP‐2 played a pivotal role, leading to subchondral sclerosis promoting further osteochondral deformities.

Since December 2019, the COVID-19 pandemic has had a significant impact on healthcare systems worldwide, prompting policymakers to implement measures of isolation and eventually adopt strict national lockdowns, which affected mobility, healthcare-seeking behavior, and services, in an unprecedented manner. This study aimed to analyze the effects of these lockdowns on hip-fracture epidemiology and care services, compared to nonpandemic periods in previous years. We retrospectively collected data from electronic patient records of two major hospitals in Western Greece and included patients who suffered a fragility hip fracture and were admitted during the two 5-week lockdown periods in 2020, compared to time-matched patients from 2017–2019. The results showed a drop in hip-fracture incidence, which varied among hospitals and lockdown periods, and conflicting impacts on time to surgery, time to discharge after surgery, and total hospitalization time. The study also found that differences between the two differently organized units were exaggerated during the COVID-19 lockdown periods, highlighting the impact of compliance with social-distancing measures and the reallocation of resources on the quality of healthcare services. Further research is needed to fully understand the specific variations and patterns of geriatric hip-fracture care during emergency health crises characterized by limited resources and behavioral changes.

After publication of this Article the authors noticed errors in several figures. In Fig. 2b the Gapdh panels are incorrect. The lysates are identical to those used in Fig. 1b, therefore the Gapdh panels should be the same in both figures. In Fig. 3b the Gapdh panels for Ad-Fhit-wt and Ad-Fhit-Y114F are incorrect and have been replaced with scans from original films. In Fig. 4A the Gapdh panels are incorrect. The lysates are identical to those used in Fig. 3b, therefore the Gapdh panels should be the same in both figures. In Fig. 4Bb the Gapdh panels for Fhit siRNA were incorrect and have been replaced with scans from original films. All resupplied figures are provided below. In Fig. 5C several panels are incorrect. The Authors were unable to locate the original films for all of these panels so Fig. 5c has been deleted. The scientific conclusions of this paper have not been affected.