Results of central ray metacarpal resection after failure of digit replantation in children.

Central ray amputation results severe esthetic blemish and functional and psychological sequelae. Three main reconstruction procedures have been reported in adults: digital translocation, intracarpal osteotomy, and metacarpal resection; none of these, however, have been studied in children. The aim of this study was to report medium-term results for treatment of central ray amputation by proximal metacarpal resection following failure of digit replantation in children (i.e., skeletally immature patients). All children consecutively operated on by metacarpal resection after failure of digit replantation for complete central ray amputation between 2012 and December 2017 were retrospectively included. The surgical procedure consisted in metacarpal resection through a palmar approach, with deep transverse metacarpal ligament reconstruction. At last follow-up, adjacent finger range of motion, pain, rotational deformity and grip strength were evaluated, as well as metacarpal laxity. Metacarpal migration index and metacarpal divergence were measured on standard X-ray. Eleven children with a mean age of 11 ± 8 years were included. At mean 18 ± 3 months' follow-up, range of motion in adjacent digits was conserved in all cases, with no intermetacarpal laxity. Grip strength was 28% lower than for the contralateral side. Two patients showed rotational malalignment in extension, without functional impairment. In 4th ray amputation (n = 8), metacarpal migration index was decreased by 65% due to radial migration of the 5th metacarpal, but metacarpal divergence was conserved in all cases. Isolated metacarpal resection of the central ray for replantation failure is a reliable and safe procedure with good radiological and functional results in skeletally immature children.

Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy.

The receptor binding protein of parainfluenza virus, hemagglutinin-neuraminidase (HN), is responsible for actively triggering the viral fusion protein (F) to undergo a conformational change leading to insertion into the target cell and fusion of the virus with the target cell membrane. For proper viral entry to occur, this process must occur when HN is engaged with host cell receptors at the cell surface. It is possible to interfere with this process through premature activation of the F protein, distant from the target cell receptor. Conformational changes in the F protein and adoption of the postfusion form of the protein prior to receptor engagement of HN at the host cell membrane inactivate the virus. We previously identified small molecules that interact with HN and induce it to activate F in an untimely fashion, validating a new antiviral strategy. To obtain highly active pretriggering candidate molecules we carried out a virtual modeling screen for molecules that interact with sialic acid binding site II on HN, which we propose to be the site responsible for activating F. To directly assess the mechanism of action of one such highly effective new premature activating compound, PAC-3066, we use cryo-electron tomography on authentic intact viral particles for the first time to examine the effects of PAC-3066 treatment on the conformation of the viral F protein. We present the first direct observation of the conformational rearrangement induced in the viral F protein.IMPORTANCE Paramyxoviruses, including human parainfluenza virus type 3, are internalized into host cells by fusion between viral and target cell membranes. The receptor binding protein, hemagglutinin-neuraminidase (HN), upon binding to its cell receptor, triggers conformational changes in the fusion protein (F). This action of HN activates F to reach its fusion-competent state. Using small molecules that interact with HN, we can induce the premature activation of F and inactivate the virus. To obtain highly active pretriggering compounds, we carried out a virtual modeling screen for molecules that interact with a sialic acid binding site on HN that we propose to be the site involved in activating F. We use cryo-electron tomography of authentic intact viral particles for the first time to directly assess the mechanism of action of this treatment on the conformation of the viral F protein and present the first direct observation of the induced conformational rearrangement in the viral F protein.

Frequency of isolated cutaneous involvement in adult mastocytosis: a cohort study.

BACKGROUND: Mastocytosis is characterized by the accumulation/proliferation of abnormal mast cells. The frequency of isolated cutaneous involvement in adults with mastocytosis has not been fully determined. The main objective of our study was to assess the frequency of isolated cutaneous mastocytosis (CM) in adults with mastocytosis skin lesions. The second objective was to compare the clinical, histological, biological and imaging features in patients with isolated CM and patients with systemic mastocytosis (SM). METHODS: We included all patients with histology-proven mastocytosis skin lesions between January 2009 and December 2017. The mastocytosis diagnosis was made according to the international diagnostic criteria. All data were collected from a dedicated specific case report. RESULTS: Among 160 patients with mastocytosis skin lesions, 25 patients had isolated CM (15.6%), 105 had SM and 30 (18.7%) patients had undetermined mastocytosis. Skin KIT mutation (OR: 51.9, 95% CI: 3.9-678, P = 0.001) and high bone marrow tryptase (OR: 97.4, 95% CI: 10.3-915, P = 0.001) were strong predictors of SM. The prevalence of osteoporosis was higher in the SM population than in the isolated CM population. Moreover, a decrease in bone mineral density over a short period of follow-up (1-2 years) was associated with SM. There were no differences between the two groups regarding the frequency of mast cell activation symptoms, the presentation of skin lesions, the number of mast cells in the dermis and the level of serum tryptase. We propose considering the KIT mutation status and bone marrow tryptase levels to aid the diagnosis of isolated CM in adult mastocytosis patients. CONCLUSION: Only a small minority of adults with mastocytosis skin lesions has isolated cutaneous involvement. In 18.7% of mastocytosis cases, even complete workup does not allow for a precise classification of patients.

Inhibiting Human Parainfluenza Virus Infection by Preactivating the Cell Entry Mechanism.

Paramyxoviruses, specifically, the childhood pathogen human parainfluenza virus type 3, are internalized into host cells following fusion between the viral and target cell membranes. The receptor binding protein, hemagglutinin (HA)-neuraminidase (HN), and the fusion protein (F) facilitate viral fusion and entry into the cell through a coordinated process involving HN activation by receptor binding, which triggers conformational changes in the F protein to activate it to reach its fusion-competent state. Interfering with this process through premature activation of the F protein has been shown to be an effective antiviral strategy in vitro. Conformational changes in the F protein leading to adoption of the postfusion form of the protein-prior to receptor engagement of HN at the host cell membrane-render the virus noninfectious. We previously identified a small compound (CSC11) that implements this antiviral strategy through an interaction with HN, causing HN to activate F in an untimely process. To assess the functionality of such compounds, it is necessary to verify that the postfusion state of F has been achieved. As demonstrated by Melero and colleagues, soluble forms of the recombinant postfusion pneumovirus F proteins and of their six helix bundle (6HB) motifs can be used to generate postfusion-specific antibodies. We produced novel anti-HPIV3 F conformation-specific antibodies that can be used to assess the functionality of compounds designed to induce F activation. In this study, using systematic chemical modifications of CSC11, we synthesized a more potent derivative of this compound, CM9. Much like CSC11, CM9 causes premature triggering of the F protein through an interaction with HN prior to receptor engagement, thereby preventing fusion and subsequent infection. In addition to validating the potency of CM9 using plaque reduction, fusion inhibition, and binding avidity assays, we confirmed the transition to a postfusion conformation of F in the presence of CM9 using our novel anti-HPIV3 conformation-specific antibodies. We present both CM9 and these newly characterized postfusion antibodies as novel tools to explore and develop antiviral approaches. In turn, these advances in both our molecular toolset and our understanding of HN-F interaction will support development of more-effective antivirals. Combining the findings described here with our recently described physiologically relevant ex vivo system, we have the potential to inform the development of therapeutics to block viral infection.IMPORTANCE Paramyxoviruses, including human parainfluenza virus type 3, are internalized into host cells by fusion between viral and target cell membranes. The receptor binding protein, hemagglutinin-neuraminidase (HN), and the fusion protein (F) facilitate viral fusion and entry into cells through a process involving HN activation by receptor binding, which triggers conformational changes in F to activate it to reach its fusion-competent state. Interfering with this process through premature activation of the F protein may be an effective antiviral strategy in vitro We identified and optimized small compounds that implement this antiviral strategy through an interaction with HN, causing HN to activate F in an untimely fashion. To address that mechanism, we produced novel anti-HPIV3 F conformation-specific antibodies that can be used to assess the functionality of compounds designed to induce F activation. Both the novel antiviral compounds that we present and these newly characterized postfusion antibodies are novel tools for the exploration and development of antiviral approaches.

Radiological and functional outcomes of high-grade spondylolisthesis treated by intrasacral fixation, dome resection and circumferential fusion: a retrospective series of 20 consecutive cases with a minimum of 2 years follow-up.

PURPOSE: Major concern during surgery for high-grade spondylolisthesis (HGS) is to reduce lumbosacral kyphosis and restore sagittal alignment. Despite the numerous methods described, lumbosacral fixation in HGS is a challenging technique associated with high complication rate. Few series have described outcomes and most of the results are limited to lumbosacral correction without global sagittal alignment analysis. This study aims at analyzing clinical and radiological outcomes of HGS patients treated with intrasacral rods on full spine radiographs. METHODS: HGS patients (Meyerding III or higher) operated between 2004 and 2014 were reviewed. All patients underwent full spine stereoradiographic images. After L5 and S1 decompression, reduction and circumferential fusion with intrasacral rod fixation and fusion up to L4 were performed under fluoroscopy. The entry points for S1 screws were located 3-5 mm above and 5 mm lateral to the first sacral hole, toward the promontory. The two short distal fusion rods were then positioned into the sacrum guided by anteroposterior fluoroscopy using Jackson's technique. Then, sacral dome resection was performed and a PEEK cage was impacted in L5S1 after reduction. Postoperatively, the hip and knee were kept flexed at 45° for 1 week and extended progressively. Preoperative, 3 months postoperative and last follow-up (> 2 years minimum) clinical and radiographic data were collected. Sagittal parameters included lumbosacral angle (LSA), olisthesis, T1 spinopelvic inclination (T1SPi) and spinopelvic parameters. RESULTS: 20 HGS patients were included (8 ptosis, 5 Meyerding IV). The mean age was 14 years. At final FU (7.2 years ± 3), LSA kyphosis and olisthesis were reduced (65° ± 14 vs 99° ± 11, p < 0.001 and 81% ± 19 vs 45% ± 18, p < 0.001, respectively). While L1L5 lordosis decreased, T1T12 kyphosis increased. At FU, global alignment with T1SPi was - 6° ± 3. No significant loss of correction was observed. Regarding complications, ten patients presented transient L5 motor deficit that occurred when patients were put in standing position. However, all recovered before 3 months postoperatively. CONCLUSION: Intrasacral rod fixation appears to be an effective technique to correct LSA kyphosis, compensatory hyperlordosis and restore global sagittal alignment with a postoperative T1SPi corresponding to the value of the asymptomatic subject and achieve fusion. However, it remains a demanding technique with high risk of transient neurologic complications.

Oncogenic FLT3-ITD supports autophagy via ATF4 in acute myeloid leukemia.

In acute myeloid leukemia (AML), internal tandem duplication mutations in the FLT3 tyrosine kinase receptor (FLT3-ITD) account for up to 25% of cases and are associated with a poor outcome. In order to better target this AML subtype, a comprehensive view of how FLT3-ITD impacts AML cell biology is required. Here, we found that FLT3-ITD expression increased basal autophagy in AML cells, and that both pharmacological and genetic inhibition of the receptor reduced autophagy in primary AML samples and cell lines. Conditional expression of shRNAs against key autophagy proteins demonstrated that autophagy is required for AML cell proliferation in vitro and for leukemic cells survival in a mouse model of xenograft. Importantly, autophagy inhibition also overcame FLT3 inhibitor resistance both in vitro and in vivo. The transcription factor ATF4 was identified as an essential actor of FLT3-ITD-induced autophagy. Cellular levels of ATF4 were highly dependent on FLT3-ITD activity, and downregulation of ATF4 inhibited autophagy-dependent AML cell proliferation and improved overall mouse survival similarly to autophagy inhibition. These results suggest that targeting autophagy or ATF4 in patients expressing FLT3 mutations may represent a novel promising and innovative therapeutic strategy for AML.

Effects of DNA Methylation on Progression to Interstitial Fibrosis and Tubular Atrophy in Renal Allograft Biopsies: A Multi-Omics Approach.

Progressive fibrosis of the interstitium is the dominant final pathway in renal destruction in native and transplanted kidneys. Over time, the continuum of molecular events following immunological and nonimmunological insults lead to interstitial fibrosis and tubular atrophy and culminate in kidney failure. We hypothesize that these insults trigger changes in DNA methylation (DNAm) patterns, which in turn could exacerbate injury and slow down the regeneration processes, leading to fibrosis development and graft dysfunction. Herein, we analyzed biopsy samples from kidney allografts collected 24 months posttransplantation and used an integrative multi-omics approach to understand the underlying molecular mechanisms. The role of DNAm and microRNAs on the graft gene expression was evaluated. Enrichment analyses of differentially methylated CpG sites were performed using GenomeRunner. CpGs were strongly enriched in regions that were variably methylated among tissues, implying high tissue specificity in their regulatory impact. Corresponding to this methylation pattern, gene expression data were related to immune response (activated state) and nephrogenesis (inhibited state). Preimplantation biopsies showed similar DNAm patterns to normal allograft biopsies at 2 years posttransplantation. Our findings demonstrate for the first time a relationship among epigenetic modifications and development of interstitial fibrosis, graft function, and inter-individual variation on long-term outcomes.

Systems Biology in Kidney Transplantation: The Application of Multi-Omics to a Complex Model.

In spite of reduction of rejection rates and improvement in short-term survival post-kidney transplantation, modest progress has occurred in long-term graft attrition over the years. Timely identification of molecular events that precede clinical and histopathological changes might help in early intervention and thereby increase the graft half-life. Evolution of "omics" tools has enabled systemic investigation of the influence of the whole genome, epigenome, transcriptome, proteome and microbiome on transplant function and survival. In this omics era, systemic approaches, in-depth clinical phenotyping and use of strict validation methods are the key for further understanding the complex mechanisms associated with graft function. Systems biology is an interdisciplinary holistic approach that focuses on complex and dynamic interactions within biological systems. The complexity of the human kidney transplant is unlikely to be captured by a reductionist approach. It appears essential to integrate multi-omics data that can elucidate the multidimensional and multilayered regulation of the underlying heterogeneous and complex kidney transplant model. Herein, we discuss studies that focus on genetic biomarkers, emerging technologies and systems biology approaches, which should increase the ability to discover biomarkers, understand mechanisms and stratify patients and responses post-kidney transplantation.

Optimising the bioreceptivity of porous glass tiles based on colonization by the alga Chlorella vulgaris.

Green façades on buildings can mitigate greenhouse gas emissions. An option to obtain green facades is through the natural colonisation of construction materials. This can be achieved by engineering bioreceptive materials. Bioreceptivity is the susceptibility of a material to be colonised by living organisms. The aim of this research was to develop tiles made by sintering granular waste glass that were optimised for bioreceptivity of organisms capable of photosynthesis. Tiles were produced by pressing recycled soda-lime glass with a controlled particle size distribution and sintering compacted samples at temperatures between 680 and 740°C. The primary bioreceptivity of the tiles was evaluated by quantifying colonisation by the algae Chlorella vulgaris (C. vulgaris), which was selected as a model photosynthetic micro-organism. Concentrations of C. vulgaris were measured using chlorophyll-a extraction. Relationships between bioreceptivity and the properties of the porous glass tile, including porosity, sorptivity, translucency and pH are reported. Capillary porosity and water sorptivity were the key factors influencing the bioreceptivity of porous glass. Maximum C. vulgaris growth and colonisation was obtained for tiles sintered at 700°C, with chlorophyll-a concentrations reaching up to 11.1±0.4µg/cm(2) of tile. Bioreceptivity was positively correlated with sorptivity and porosity and negatively correlated with light transmittance. The research demonstrates that the microstructure of porous glass, determined by the processing conditions, significantly influences bioreceptivity. Porous glass tiles with high bioreceptivity that are colonised by photosynthetic algae have the potential to form carbon-negative façades for buildings and green infrastructure.

Return to recreational sport and clinical outcomes with at least 2years follow-up after arthroscopic repair of rotator cuff tears.

INTRODUCTION: The main objective of the study was to assess return to sports in recreational athletes after arthroscopic repair of rotator cuff tear (RCT). MATERIAL AND METHODS: A retrospective single-center study included all recreational athletes operated between 2008 and 2012 for arthroscopic repair of RCT, with regular sports activity, and aged less than 70 years. All were recontacted at a minimum follow-up of 2 years. The main outcome was return to sports (yes/no). The secondary criteria were return to sports, time to return to sports, number of hours per week of sports activity, and at the last follow-up the subjective assessment of sports level, patient satisfaction, and the Western Ontario Rotator Cuff (WORC) Index. RESULTS: Seventy-six patients (37 females, 39 males) with a mean age of 57.0±7.3 years were included. Of these 76 patients, 53 (69.7%) patients participated in a sport that specifically involved the upper limb. The mean follow-up was 45±14 months. Postoperatively, 67 of 76 (88.2%) patients returned to a sports activity, the same sport for 52 out of 76 (68.4%). The mean time to return to sports was 6±4.9 months. For patients who had taken up their sport again, the mean number of hours a week was not significantly modified (P=0.58). At the last follow-up, the subjective sports level was judged better or identical to the preoperative level by 52 of 67 (77.6%) patients. The factors significantly associated with absence of return to the previous sport were pain symptoms evolving for more than 9 months before surgery (OR=3.6 [1.01-12.5], P=0.04) and preoperative sports intensity less than 2h/week (OR=4.1 [1.4-12.3], P=0.01). At the last follow-up, the functional improvement evaluated by the WORC Index was strongly significant (P<0.00001) and 73 of 76 (96%) patients were satisfied. CONCLUSION: The majority of the recreational athletes returned to sports after arthroscopic rotator cuff repair, most often at the same level and with equivalent intensity compared to before surgery. LEVEL OF EVIDENCE: IV, retrospective study.

Evaluation of molecular profiles in calcineurin inhibitor toxicity post-kidney transplant: input to chronic allograft dysfunction.

The molecular basis of calcineurin inhibitor toxicity (CNIT) in kidney transplantation (KT) and its contribution to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA) were evaluated by: (1) identifying specific CNIT molecular pathways that associate with allograft injury (cross-sectional study) and (2) assessing the contribution of the identified CNIT signature in the progression to CAD with IF/TA (longitudinal study). Kidney biopsies from well-selected transplant recipients with histological diagnosis of CNIT (n = 14), acute rejection (n = 13) and CAD with IF/TA (n = 10) were evaluated. Normal allografts (n = 18) were used as controls. To test CNIT contribution to CAD progression, an independent set of biopsies (n = 122) from 61 KT patients collected at 3 and ~12 months post-KT (range = 9-18) were evaluated. Patients were classified based on 2-year post-KT graft function and histological findings as progressors (n = 30) or nonprogressors to CAD (n = 31). Molecular signatures characterizing CNIT samples were identified. Patients classified as progressors showed an overlap of 7% and 22% with the CNIT signature at 3 and at ~12 months post-KT, respectively, while the overlap was <1% and 1% in nonprogressor patients, showing CNIT at the molecular level as a nonimmunological factor involved in the progression to CAD.

Pim kinases phosphorylate Chk1 and regulate its functions in acute myeloid leukemia.

Phosphorylation by Akt on Ser 280 was reported to induce cytoplasmic retention and inactivation of CHK1 with consequent genetic instability in PTEN-/- cells. In acute myeloid leukemia cells carrying the FLT3-internal tandem duplication (ITD) mutation, we observed high rates of FLT3-ITD-dependent CHK1 Ser 280 phosphorylation. Pharmacological inhibition and RNA interference identified Pim1/2, not Akt, as effectors of this phosphorylation. Pim1 catalyzed Ser 280 phosphorylation in vitro and ectopic expression of Pim1/2-induced CHK1 phosphorylation. Ser 280 phosphorylation did not modify CHK1 localization, but facilitated its cell cycle and resistance functions in leukemic cells. FLT3, PIM or CHK1 inhibitors synergized with DNA-damaging agents to induce apoptosis, allowing cells to bypass the etoposide-induced G2/M arrest. Consistently, etoposide-induced CHK1-dependent phosphorylations of CDC25C on Ser 216 and histone H3 on Thr11 were decreased upon FLT3 inhibition. Accordingly, ectopic expression of CHK1 improved the resistance of FLT3-ITD cells and maintained histone H3 phosphorylation in response to DNA damage, whereas expression of unphosphorylated Ser 280Ala mutant did not. Finally, FLT3- and Pim-dependent phosphorylation of CHK1 on Ser 280 was confirmed in primary blasts from patients. These results identify a new pathway involved in the resistance of FLT3-ITD leukemic cells to genotoxic agents, and they constitute the first report of CHK1 Ser 280 regulation in myeloid malignancies.

Impact of calcineurin-inhibitor conversion to mTOR inhibitor on renal allograft function in a prednisone-free regimen.

Traditionally, chronic calcineurin inhibitor (CNI) nephrotoxicity has been considered to be one of the main nonimmune mechanisms causing chronic renal allograft dysfunction. CNI minimization and withdrawal strategies have yielded inconsistent results. Few studies address the feasibility of CNI elimination in a prednisone-free regimen. We report a prospective, randomized trial in 200 patients evaluating the impact on renal function and incidence of acute rejection after conversion from tacrolimus (Tac) to sirolimus (SRL). Patients with recent (<3 months) acute rejection episodes or with >0.5 g/day of proteinuria were excluded. All were induced with alemtuzumab, underwent rapid steroid elimination and were maintained on mycophenolate mofetil and Tac. At 12 months posttransplant, patients were randomized 2:1 to SRL (n = 123) or maintained on Tac (n = 64). Mean follow-up was 41.1 ± 15.8 months in the SRL group and 40.7 ± 14.4 months in the Tac group. Biopsy-proven acute rejection at 24 months postrandomization was similar between the groups. Patient survival, graft survival and estimated GFR were also not statistically different. Our study demonstrates that in a prednisone-free immunosuppressive regimen, conversion from Tac to SRL at 12 months posttransplantation is not associated with increased rates of acute rejection and graft loss. However, despite CNI elimination, renal allograft function is equally maintained in both groups.

[Metacarpal osteoarticular injuries in children]. / Traumatismes ostéoarticulaires des métacarpiens chez l'enfant.

Metacarpal fractures and dislocations in the fingers are common injuries in children's hands. Most of these can be treated successfully non-operatively, although a subset requires more aggressive treatment. Results following appropriate care in children are generally good. Twenty percent of them need a reduction, need for surgical stabilization is rare. Each injury is presented, including diagnostic, therapeutic principles, pitfalls to prevent and potential complications.

MicroRNA signature at the time of clinical HCV recurrence associates with aggressive fibrosis progression post-liver transplantation.

Diagnosis and prediction of the severity of hepatitis C virus recurrence (HCVrec) after liver transplantation (LT) remain a challenge. MicroRNAs have been recently recognized as potential disease biomarkers. Archival liver biopsy samples from 43 HCV+ LT recipients were collected at clinical HCVrec time and at 3 years post-LT. Patients were classified as progressors (P = F0/F1) or nonprogressors (NP = F3/F4) according to the severity of fibrosis on the 3-year biopsy. Training (n = 27) and validation (n = 16) sets were defined. RNA was isolated from all biopsies at clinical HCVrec time, labeled and hybridized to miRNA-arrays. Progressors versus nonprogressors were compared using the two-sample t-test. A p-value ≤0.01 was considered significant. The ingenuity pathway analysis tool was used for microRNA and miRNA:mRNA ontology data integration. Nine microRNAs were differentially expressed between groups. A supervised cluster analysis separated samples in two well-defined groups (progressors vs. nonprogressors). Pathway analysis associated those microRNAs with hepatitis, steatosis, fibrosis, cirrhosis and T cell-related immune response. Data integration identified 17 genes from a previous genomic study as 9-microRNAs signature targets. Seven microRNAs were successfully validated in the validation set using QPCR. We have identified a 9-microRNA signature able to identify early post-LT patients at high risk of severe HCVrec during long-term follow-up.

The short form of RON is expressed in acute myeloid leukemia and sensitizes leukemic cells to cMET inhibitors.

Several receptor tyrosine kinases (TKs) are involved in the pathogenesis of acute myeloid leukemia (AML). Here, we have assessed the expression of the Recepteur d'Origine Nantais (RON) in leukemic cell lines and samples from AML patients. In a series of 86 AML patients, we show that both the full length and/or the short form (sf) of RON are expressed in 51% and 43% of cases, respectively. Interestingly, sfRON is not expressed in normal CD34+ hematopoietic cells and induces part of its oncogenic signaling through interaction with the Src kinase Lyn. sfRON-mediated signaling in leukemic cells also involves mTORC1, the proapoptotic bcl2-family member, BAD, but not the phosphatidylinositol 3-kinase/Akt pathway. Furthermore, the expression of sfRON was specifically downregulated by 5-azacytidine (AZA). Conversely, AZA could induce the expression of sfRON in sfRON-negative leukemic cells suggesting that the activity of this drug in AML and myelodysplastic syndromes could involve modulation of TKs. cMET/RON inhibitors exhibited an antileukemic activity exclusively in AML samples and cell lines expressing sfRON. These results might support clinical trials evaluating cMET/RON inhibitors in AML patients expressing sfRON.

MicroRNAs as biomarkers in solid organ transplantation.

Important progress has been made in improving short-term outcomes in solid organ transplantation. However, long-term outcomes have not improved during the last decades. There is a critical need for biomarkers of donor quality, early diagnosis of graft injury and treatment response. MicroRNAs (miRNAs) are a class of small single-stranded noncoding RNAs that function through translational repression of specific target mRNAs. MiRNA expression has been associated with different diseases and physiological conditions. Moreover, miRNAs have been detected in different biological fluids and these circulating miRNAs can distinguish diseased individuals from healthy controls. The noninvasive nature of circulating miRNA detection, their disease specificity and the availability of accurate techniques for detecting and monitoring these molecules has encouraged a pursuit of miRNA biomarker research and the evaluation of specific applications in the transplant field. miRNA expression might develop as excellent biomarkers of allograft injury and function. In this minireview, we summarize the main accomplishments of recently published reports focused on the identification of miRNAs as biomarkers in organ quality, ischemia-reperfusion injury, acute rejection, tolerance and chronic allograft dysfunction emphasizing their mechanistic and clinical potential applications and describing their methodological limitations.