A new matrikine-derived peptide up-regulates longevity genes for improving extracellular matrix architecture and connections of dermal cell with its matrix.

OBJECTIVE: Skin extracellular matrix (ECM) is a dense and well-organized structure produced by fibroblasts. This ECM transduces environmental mechano-signals to cell nucleus through the integrin-actin complex, thus triggering ECM protein syntheses. The aim of this study was to discover a novel peptide, structurally related to dermal matrikines, that promotes syntheses of ECM components. METHODS AND RESULTS: Screening tests with 120 peptides were carried out by using normal dermal human fibroblasts (HF). As a result, one candidate of interest was isolated, the N-Prolyl Palmitoyl Tripeptide-56 Acetate (PP56), which increases collagen and fibronectin productions at gene and/or protein levels. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), a recent and innovative analytical technology, in addition to more traditional techniques, it was showed that two metabolic pathways were significantly modulated: one for collagen production and one for actin. Moreover, this peptide up-regulated the transcription of Forkhead Box O (FOXO) and sestrin messenger RNAs (mRNA), leading to production of proteins involved into longevity and more recently in collagen production. RESULTS: Results indicated that this peptide is a potential candidate to improve ECM density and organization in a new way.

OBJECTIF: La matrice extracellulaire cutanée (MEC) est une structure dense et bien organisée produite par les fibroblastes. Cette MEC transduit les mécano-signaux environnementaux vers le noyau de la cellule par le biais du complexe intégrine-actine, ce qui déclenche la synthèse de protéines par la MEC. Le but de cette étude était de découvrir un nouveau peptide, structurellement apparenté aux matrikines dermiques, qui favorise la synthèse des composants de la MEC. MÉTHODES ET RÉSULTATS: Des tests de criblage avec 120 peptides ont été réalisés en utilisant des fibroblastes humains dermaux normaux (HF). Un candidat d'intérêt a été isolé, l'acétate de N-Prolyl Palmitoyl-Tripeptide-56 (PP56), qui augmente les productions de collagène et de fibronectine aux niveaux du gène et / ou de la protéine. En utilisant une technologie analytique récente et innovante, la spectrométrie de masse par chromatographie liquide-tandem (LC-MS / MS) ainsi que des techniques plus traditionnelles, il a été démontré que deux voies métaboliques sont modulées de manière significative: une pour la production de collagène et une pour l'actine. En outre, ce peptide a régulé positivement la transcription des ARN messagers (ARNm), du facteur de transcription Forkhead Box (FOXO) et de la sestrine, conduisant à la production de protéines impliquées dans la longévité et plus récemment dans la production de collagène. RÉSULTATS: Les résultats ont indiqué que ce peptide est un candidat potentiel pour améliorer la densité et l'organisation de la MEC d'une manière nouvelle.

Reduced-intensity versus reduced-toxicity myeloablative fludarabine/busulfan-based conditioning regimens for allografted non-Hodgkin lymphoma adult patients: a retrospective study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

BACKGROUND: Fludarabine/busulfan-based conditioning regimens are widely used to perform allogeneic stem-cell transplantation (allo-SCT) in high-risk non-Hodgkin lymphoma (NHL) patients. The impact of the dose intensity of busulfan on outcomes has not been reported yet. PATIENTS AND METHODS: This was a retrospective with the aim to compare the outcomes of NHL patients who received before allo-SCT a fludarabine/busulfan conditioning regimen, either of reduced intensity (FB2, 2 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 277) or at a myeloablative reduced-toxicity dose (FB3/FB4, 3 or 4 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 101). RESULTS: In univariate analysis, the 2-year overall survival (FB2 66.5% versus 60.3%, P = 0.33), lymphoma-free survival (FB2 57.9% versus 49.8%, P = 0.26), and non-relapse mortality (FB2 19% versus 21.1%, P = 0.91) were similar between both groups. Cumulative incidence of grade III-IV acute graft versus host disease (GVHD) (FB2 11.2% versus 18%, P = 0.08), extensive chronic GVHD (FB2: 17.3% versus 10.7%, P = 0.18) and 2-year GVHD free-relapse free survival (FB2: 44.4% versus 42.8%, P = 0.38) were also comparable. In multivariate analysis there was a trend for a worse outcome using FB3/FB4 regimens (overall survival: HR 1.47, 95% CI: 0.96-2.24, P = 0.08; lymphoma-free survival: HR: 1.43, 95% CI: 0.99-2.06, P = 0.05; relapse incidence: HR 1.54; 95% CI: 0.96-2.48, P = 0.07). These results were confirmed using a propensity score-matching strategy. CONCLUSION: We conclude that reduced toxicity myeloablative conditioning with fludarabine/busulfan does not improve the outcomes compared with reduced-intensity conditioning in adults receiving allo-SCT for NHL.

Polarization mechanisms of dielectric materials at a binary liquid interface: impacts on electrowetting actuation.

We explored polarization mechanisms at the interface between a dielectric material (an electrolyte) and an insulating liquid, during electrowetting actuation. Native surface charge density due to hydrophobic coating has been measured as an offset voltage for which the contact angle is at its minimum. Surface charge densities as low as 0.023 mC m-2 have been measured using this method, demonstrating that electrowetting can be used as a probe to measure native surface charge density. This effect strongly differs depending on the kind of polarization and is at the origin of major discrepancies between alternative and direct polarization during electrowetting actuation. A new model describing electrowetting actuation is also proposed, leading to a more predictive description as well as useful recommendations on materials to obtain a stable actuation under DC polarization.

Lymphoma occurring in patients over 90 years of age: characteristics, outcomes, and prognostic factors. A retrospective analysis of 234 cases from the LYSA.

BACKGROUND: Lymphoma occurring in patients aged 90 or older is not uncommon, and its incidence is expected to increase over time. Management of these patients is difficult given their underlying fragility and the lack of information regarding this population. PATIENTS AND METHODS: We retrospectively analyzed 234 patients diagnosed with lymphoma at the age of 90 years or older (90+) between 1990 and 2012 to describe their characteristics, management, outcomes and prognostic factors. RESULTS: The median age was 92 years; 88% were B-cell lymphomas consisting mainly in diffuse large B-cell lymphoma. The median overall survival (OS) was 7.2 months (range, 0-92 months) for the 227 patients with non-Hodgkin Lymphoma (NHL), with a significant difference between aggressive and indolent NHL (5.2 months versus 19.4 months, respectively). We further analyzed 166 NHL patients for whom detailed characteristics were available. Among these patients, 63.5% received a treatment, either local (7.5%) or systemic (56%). Lymphoma was reported as the main cause of death (40%). Treatment administration was associated with improved OS in patients with aggressive (P < 0.001) but not indolent NHL (P = 0.96). In patients with aggressive NHL, hypoalbuminemia appeared as a strong and independent negative prognostic factor. CONCLUSIONS: The median OS is short in 90+ patients diagnosed with lymphoma but some patients experience prolonged survival. Lymphoma represents the main cause of death in these patients. Treatment may improve survival of selected patients with aggressive but not indolent NHL. Management of these patients may be guided by prognostic factors identified in this study, notably serum albumin.

Large granular lymphocyte leukemia: An indolent clonal proliferative disease associated with an array of various immunologic disorders.

Large granular lymphocyte leukemia (LGLL) is a chronic lymphoproliferative disorder characterized by the proliferation of T or NK cytotoxic cells in the peripheral blood, the spleen and the bone marrow. Neutropenia leading to recurrent infections represents the main manifestation of LGLL. One specificity of LGLL is its frequent association with auto-immune disorders, among them first and foremost rheumatoid arthritis, and other hematologic diseases, including pure red cell aplasia and bone marrow failure. The large spectrum of manifestations and the classical indolent course contribute to the diagnosis difficulties and the frequency of underdiagnosed cases. Of importance, the dysimmune manifestations disappear with the treatment of LGLL as the blood cell counts normalize, giving a strong argument for a pathological link between the two entities. The therapeutic challenge results from the high rate of relapses following the first line of immunosuppressive drugs. New targeted agents, some of which are currently approved in autoimmune diseases, appear to be relevant therapeutic strategies to treat LGLL, by targeting key activated pathways involved in the pathogenesis of the disease, including JAK-STAT signaling.

Reduced-intensity and non-myeloablative allogeneic stem cell transplantation from alternative HLA-mismatched donors for Hodgkin lymphoma: a study by the French Society of Bone Marrow Transplantation and Cellular Therapy.

Allogeneic stem cell transplantation (allo-SCT) following a non-myeloablative (NMA) or reduced-intensity conditioning (RIC) is considered a valid approach to treat patients with refractory/relapsed Hodgkin lymphoma (HL). When an HLA-matched donor is lacking a graft from a familial haploidentical (HAPLO) donor, a mismatched unrelated donor (MMUD) or cord blood (CB) might be considered. In this retrospective study, we compared the outcome of patients with HL undergoing a RIC or NMA allo-SCT from HAPLO, MMUD or CB. Ninety-eight patients were included. Median follow-up was 31 months for the whole cohort. All patients in the HAPLO group (N=34) received a T-cell replete allo-SCT after a NMA (FLU-CY-TBI, N=31, 91%) or a RIC (N=3, 9%) followed by post-transplant cyclophosphamide. After adjustment for significant covariates, MMUD and CB were associated with significantly lower GvHD-free relapse-free survival (GRFS; hazard ratio (HR)=2.02, P=0.03 and HR=2.43, P=0.009, respectively) compared with HAPLO donors. In conclusion, higher GRFS was observed in Hodgkin lymphoma patients receiving a RIC or NMA allo-SCT with post-transplant cyclophosphamide from HAPLO donors. Our findings suggest they should be favoured over MMUD and CB in this setting.

Allogeneic stem cell transplantation for patients with mantle cell lymphoma who failed autologous stem cell transplantation: a national survey of the SFGM-TC.

Poly-chemotherapy plus rituximab followed by autologous stem cell transplantation (auto-SCT) is standard care for untreated young patients with mantle cell lymphoma (MCL). Despite this intensive treatment, transplant patients remain highly susceptible to relapse over time. The French SFGM-TC performed a national survey on reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) for fit relapsed/refractory patients who failed after auto-SCT (n=106). Median times of relapse after auto-SCT, and from auto-SCT to RIC-allo-SCT were 28 months and 3.6 years, respectively. Sixty per cent of patients received at least three lines of treatment before RIC-allo-SCT. Conditioning regimens for RIC-allo-SCT were heterogeneous. Twenty patients experienced grade III/IV aGvHD, extensive cGvHD was reported in 28 cases. Median follow-up after RIC-allo-SCT was 45 months. Median PFS after RIC-allo-SCT was 30.1 months and median overall survival was 62 months. Treatment-related mortality (TRM) at 1 year and 3 years were estimated at 28% and 32%, respectively. A total of 52 patients died; major causes of death were related to toxicity (n=34) and MCL (n=11). Patients in good response before RIC-allo-SCT experienced a better PFS and OS. Our work highlights the need for new RIC-allo-SCT MCL-tailored approaches to reduce TRM, and early and late relapse.

Peripheral blood flow responses to exercise after successful correction of coarctation of the aorta.

OBJECTIVES: The purpose of this study was to characterize peripheral flow kinetics in response to progressive discontinuous maximal exercise in 10 patients who underwent repair of coarctation of the aorta and 11 age-matched healthy adolescents. BACKGROUND: An impairment of leg blood flow has been suggested on the basis of exaggerated femoral muscle lactate accumulation in patients with successful repair of coarctation. Few data are available describing blood flow kinetics of the exercising leg in such patients. METHODS: Duplex ultrasound provided transcutaneous measurements of peak systolic and end-diastolic flow velocities of the femoral, humeral and renal arteries at rest and immediately after mild, moderate and maximal exercise intensities for computation of mean velocity, resistance index and femoral blood flow. RESULTS: Femoral mean velocity and femoral blood flow increased linearly with exercise intensity in both groups, but the slope of this increase was significantly lower in patients. Similarly, humeral mean velocity increased significantly less in patients than in control subjects. Femoral resistance index sharply decreased from that at rest (patients [mean +/- SE] 1.4 +/- 0.04; control subjects 1.4 +/- 0.03) to mild exercise intensity in both groups (patients 0.69 +/- 0.03; control subjects 0.72 +/- 0.03). A further decrease was observed at maximal exercise in patients (0.60 +/- 0.04, p = 0.08) but not in control subjects (0.69 +/- 0.02). CONCLUSIONS: These observations suggest that despite a greater exercise-induced femoral vasodilation, patients with successful correction of coarctation of the aorta demonstrate an impaired lower limb blood flow in response to strenuous dynamic exercise. In the absence of stenosis at rest, this alteration could result from exaggerated flow turbulence in the descending aorta distal to the site of correction because of loss of elasticity at the site of the resection of the coarcted segment.

Predictive factors for spontaneous closure of atrial septal defects diagnosed in the first 3 months of life.

OBJECTIVES: To establish the rate of spontaneous closure of atrial septal defects diagnosed before age 3 months, 101 infants (mean age 26 days) with an interatrial shunt confirmed by Doppler echocardiography were followed up for an average of 265 +/- 190 days. BACKGROUND: Even if interatrial shunts in the newborn are frequently encountered, little is known about their natural history. METHODS: Defect diameter on two-dimensional echocardiography and width of color flow jet were measured in the subcostal view. Right and left ventricular diameters and atrial septal curvature were also studied. Kaplan-Meier curves were obtained to predict age of spontaneous closure in relation to initial defect diameter. RESULTS: There was no significant correlation between the diameter of the atrial septal defect and right ventricular/left ventricular ratio or type of septal curvature (vertical or concave toward the left atrium). The classic predominance of girls over boys was observed only for defects > 5 mm. An overall rate of spontaneous closure of 87% was observed. Frequency and timing of closure were inversely correlated to atrial septal defect diameter: closure occurred in 100% (32 of 32) of defects in group 1 (diameter < 3 mm), 87% of defects (39 of 45) in group 2 (diameter 3 to 5 mm), 80% of defects (16 of 20) in group 3 (diameter 5 to 8 mm). Spontaneous closure did not occur in four patients of group 4 (defect > or = 8 mm) during an average follow-up interval of 417 days (range 294 to 597 days). CONCLUSIONS: These results suggest that infants with an atrial septal defect < 3 mm need not be followed up as 100% of these defects will be closed by age 18 months; those with a defect 3 to 5 or 5 to 8 mm should be evaluated by the end of the 12th and the 15th month, respectively, when > 80% of these defects will be closed. An atrial septal defect with a diameter > or = 8 mm may have little chance of closing spontaneously and the possibility of surgical correction should be considered. Defects < 3 mm probably do not constitute a cardiac malformation in light of their natural evolution and gender distribution.

Use of acetylsalicylic acid to improve patency of subclavian to pulmonary artery Gore-Tex shunts.

In order to assess the influence of acetylsalicylic acid (ASA) on function and patency of Gore-Tex shunts, angiographic features of 62 Gore-Tex shunts were assessed, 31 without and 31 with postoperative ASA. Groups were selected on the basis of similar angiographic follow-up duration. Mean follow-up was 709 days for the group without ASA and 739 days for the group with it. The average daily dose of ASA was 4.5 mg/kg/day started a mean of 6.7 days after surgery. Clinical characteristics were similar between the two groups except for age at surgery which was 581 days in the group without ASA (operated between 1983 and 1987) and 303 days in the group with (operated between 1987 and 1991), reflecting the fact that patients were operated upon earlier after 1987. Preoperative Gore-Tex diameter was similar between the two groups, but three patients in the group with ASA had a Gore-Tex shunt as small as 4 mm. At angiography, four conduits were diagnosed as nonpatient (two in each group), 20 had a localized stenosis (11 of 28 in the group without ASA and nine of 23 in the group with ASA). Patency index (angiographic Gore-Tex diameter/preoperative Gore-Tex diameter) was similar in the two groups: 68.5% in the group without ASA and 69.7% in the group with ASA. Pulmonary artery growth index was 57% in the group without ASA and 91% in the group with ASA. No risk factor for thrombosis or decreased patency was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Gallstone fragmentation during biliary lithotripsy: effect of stone composition and structure.

In vitro lithotripsy with the Siemens Lithostar was conducted on 36 radiolucent or minimally calcified gallstones housed in an anthropomorphic phantom. The ease and pattern of fragmentation were correlated with global composition for the entire stone, regional or microcomposition (determined by Fourier-transform infrared spectroscopy), and microstructure (determined by scanning electron microscopy). Stones made up of more than 62% cholesterol required 50% more shock waves to pulverize all fragments to 0.3 cm or less than did stones of less than 62% cholesterol (p less than .01). An inverse relationship was found between the number of shock waves needed for fragmentation and the cholesterol content (r = .77). Although a broad range of fragmentation responses occurred, little variation was seen in the ease of fragmentation within stone families. The majority of stones fractured along radially oriented cholesterol plates, but one third of stones treated showed initial chipping or flaking at the periphery before radial fracture. This type of peripheral erosion most often occurred in stones with peripheral pigment rims. These stones required more shock waves and lagged in pulverization compared with more homogeneous cholesterol stones. The efficiency of fragmentation during biliary lithotripsy correlates with the stones' global cholesterol content. A stone's architecture, as reflected by its regional composition and microstructure, partially predicts the mechanism of fragmentation. These in vitro data may be useful in further refining criteria for selecting patients and understanding the fragmentation process.