Full Intensity Research Articles

Mixed Chimerism at Three Months after Allogeneic Hematopoietic Stem Cell Transplantation Is a Significant Predictor of Disease Relapse in High-Risk Acute Myeloid Leukemia Patients in First Complete Remission

Background:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative strategy for high-risk acute myeloid leukemia (AML) patients. However, the risk for disease recurrence following allo-HSCT remains significant and associated with poor outcomes. The ability to predict relapse before detectable morphologic recurrence may allow for preemptive interventions, such as immune modulation, donor lymphocyte infusion (DLI), or initiation of hypomethylating agents, to potentially augment graft-versus-leukemia effect. Post-transplantation peripheral blood chimerism analysis, represents a potential tool to predict disease recurrence, although a validated consensus on the use of this technique in the post-allo-HSCT follow-up has not been established yet and its precise role in this setting remains unclear. The aim of our study is to evaluate the impact of chimerism evaluation 3 months after allo-HSCT in AML patients who were in first complete remission (CR1) before transplantation and remained in clinical and morphological CR at day 90 post-transplantation, on overall survival (OS) and relapse incidence.Patients and methods:We evaluated 194 AML patients who received allo-HSCT at our center between January 2006 and December 2014 and for whom chimerism follow-up has been performed at 3 months. There were 103 (53%) males and 91 (47%) females with a median age of 43 years (range: 18-67). Patients were classified according to the European LeukemiaNet classification for cytogenetic and molecular biology markers (Dohner et al. Blood 2010), accordingly, 64% patients were unfavorable and 36% were in intermediate II risk group. At allo-HSCT, all patients were in CR1; 136 (70%) received a full intensity conditioning (MAC) and 58 (30%) received a reduced intensity conditioning (RIC). HSC donors were 72 (37%) HLA identical siblings (44 BM and 36 PBSC), 54 (28%) 10/10 HLA matched unrelated donors (35 BM and 19 PBSC), 33 (17%) 9/10 HLA mismatched unrelated donors (16 BM and 17 PBSC) and 35 (18%) double cord blood units (only 7 were 6/6 HLA matched). Chimerism analysis was performed on marrow and/or blood samples every month following allo-HSCT using polymerase chain reaction (PCR) based on informative polymorphic short tandem repeat, a mixed chimerism was defined by having 5% or more of recipient cells.Results:At day 90 after transplantation, all patients remained in clinical and cytological CR at time of chimerism evaluation, 155 (80%) had a full donor chimersim (FDC) and 39 (20%) had a mixed chimerism (MC) ranging from 65% to 95% of donor cells. Among patients with MC, 9 (23%) received increasing doses of DLI (5 of them reached FDC at 6 months), while 20 (51%) could not receive DLI (7 because transplanted from cord blood, and 13 because of the presence of GVHD), the rest of patients were left with a transient MC and regained FDC during follow-up.After a median follow-up of 34 months (range: 4-96) for the surviving patients, the median OS in patients with FDC was not reached with a 3 years probability of 62% (95% CI: 58-66), and for patients with MC, it was 18 months (12-24) with a 3 years probability of 32% (95% CI: 23-41), (p=0.01). Twenty-two patients in the MC group have progressed during the follow-up and 17 among them died from disease progression. The cumulative incidence of relapse at 3 years was 25% (95% CI: 21-29) for FDC patients and it was 70% (95% CI: 62-80) for MC patients, (p<0.001). The impact of mixed chimerism was still valid in multivariate analysis after including patient age, type of donor, HSC source and risk group, and was independent from the intensity of the conditioning regimen with a Hazard Ratio of 4.7, and a 95% CI: 2.6-8.4, p<0.001.Conclusion:We demonstrated that chimerism evaluation at day 90 after allo-HSCT is an independent predictor of disease relapse in patients who remain in CR at that time and significantly impacts on long term survival. The standardization of this evaluation may lead to the identification of patients with high-risk of relapse risk suggesting the need of early preemptive intervention. [Display omitted] DisclosuresNicolini:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Thymoglobulin Does Not Impact Relapse or Survival after Matched Unrelated Transplantation for AML/MDS Compared to Matched Related Donor Transplantation without Thymoglobulin Use

▪Thymoglobulin does not impact relapse or survival after matched unrelated transplantation for AML/MDS compared to matched related donor transplantation without Thymoglobulin use.Background: Thymoglobulin has been used customarily after matched related (RD) and unrelated (MUD) hematopoietic stem cell transplantation (HCT) to decrease risk of GVHD and graft rejection. However, its use has been implicated in increasing the risk of relapse. As matched sibling related donors considered the best available donor source for patients with AML /MDS, we hypothesized that production of outcomes (Relapse/Survival) after MUD transplant with use of thymoglobulin similar to RD transplantation without the use of thymoglobulin, would justify the use of thymoglobulin after MUD HCT in AML/MDS.Method: We compared the outcomes of 98 (29 matched RD/ 69 matched MUD) consecutive patients with AML/MDS who underwent HCT with Fludarabine/ Busulfan based conditioning between 7/2009-12/2014. Patients Characteristics are shown in Table-1. Patients received full intensity conditioning (FIC) with Fludarabine 40 mg/m2 for 4 days and Busulfan 3.2 mg/Kg single daily dose for 4 days (AUC 4200-5000). GVHD prophylaxis for FIC was Tacrolimus/mini Methotrexate and Tacrolimus/Mycophenolate for RIC. Thymoglobulin was added at dose of 1.5 mg/Kg for 3 days for MUD patients only regardless the conditioning intensity.Results: With median follow up 696 days (RD 746 days, MUD 676 days), the overall survival at 1 year was 75% +/- 8% and 74% +/- 5% for RD and MUD respectively, P=0.66. All patient engrafted except two patients in FIC MUD group. The cumulative incidence of relapse at 1 year was 31% +/- 8% and 23% +/- 5% for RD & MUD respectively, while the treatment related mortality (TRM) was 3.5% +/- 3% and 10% +/- 3% for RD and MUD HCT recipients. Cumulative Incidence acute GVHD grade II-1V was 29% in RD and 49% in MUD. Grade III-IV acute GVHD was 14% in Both RD and MUD recipients. Higher cumulative incidence of extensive chronic GVHD was observed in MUD recipients of 28% vs 20% in RD recipients.Conclusion: The addition of thymoglobulin to MUD HCT did not increase the cumulative incidence of relapse compared to RD HCT patients who did not receive thymoglobulin. RD HCT remained associated with lower TRM than MUD HCT despite the addition of thymoglobulin. MUD HCT with thymoglobulin produced similar overall survival to RD HCT without thymoglobulin. Our data suggest continued use of low dose thymoglobulin with MUD HCT while avoiding its use with matched RD HCT. Table 1PatientsRelated DonorUnrelated DonorNumber2969AML2261MDS78Graft Failure02Age (Range)53 (35-71)56 (25-73)Reduced Intensity825Full Intensity2144CR11747CR245Relapsed/Refractory817 DisclosuresNo relevant conflicts of interest to declare.

Analysis of the methods for determining the indicators of energy efficiency

The indicators of energy efficiency and methods for determining energy consumption for the manufacture of production (services) are discussed: standard for determining the full energy intensity (Ukrainian and Russian version); algorithm for determining technological energy intensity; method of determining the guild, full guild and factory (through) energy intensity. It is given a comparison of different types of the energy intensity of production

Emotion recognition and alexithymia in high functioning females with autism spectrum disorder

Although there is a wealth of information on the emotion recognition skills of males with autism spectrum disorders (ASD), not much is known about these skills in women with ASD. This study investigates the relation between alexithymia and emotion recognition in this group. 31 high-functioning females with ASD and 28 age matched typical females performed a vocal and visual emotion recognition task and completed an alexithymia questionnaire. Level of intensity of the presented emotions was manipulated in the visual emotion recognition task between 25% (low intensity) and 100% (full emotion intensity) in 25% increments. There was no evidence of impairments in the accuracy of visual or vocal emotion recognition. Both groups were equally affected by level of intensity. Level of alexithymia was higher in women with ASD in the cognitive domain. Within the ASD group, women with high levels of alexithymia attained lower scores on visual emotion recognition in the lowest intensity condition, suggesting that being able to identify one's own emotions may help in processing subtle emotions.

High performance dye-sensitized solar cells with inkjet printed ionic liquid electrolyte

We successfully inkjet printed an ionic liquid electrolyte in the dye-sensitized solar cell (DSSC) as a part of a new cell fabrication sequence that eliminates drilling holes in the DSSC substrates. The inkjet printing of ionic liquid electrolyte does not only reduce the overall fabrication cost since no additional thermoplastic sealant and glass cover are required to seal the cells, but also removes one extra cell sealing step present in the traditional cell sealing process. The dye-sensitized DSSCs fabricated with printed electrolyte exhibited 6% enhancement in overall cell conversion efficiency compare to the reference cells. More significantly, the printed electrolyte based solar cells maintained 100% of the initial performance in an accelerated ageing test for 1120h that was performed under full sun light intensity at 35°C. These results provide a solid base to develop this process further for the production of cheaper, more robust, large area DSSC solar panels.

Minimal-Energy Control Sequences for Linear Multi-Primary Displays

A control sequence gives the intensities of the primaries for a pixel in a display. A multi-primary display has four or more primaries, so that multiple control sequences can sometimes produce the same color. Different primaries likely consume different amounts of energy; furthermore, the energy consumption can be a complicated function. A minimal-energy control sequence for a target color produces that color with as little energy as possible. This article shows that such minimal-energy sequences take a simple geometric form when each primary&#x2019;s energy function is linear. The display gamut, in CIE XY Z space, can be dissected into parallelepipeds. The originating vertex of each parallelepiped is the sum of a set of primaries at full intensity. Each edge of a parallelepiped is the translation of one primary. A color with XYZ coordinates in a certain parallelepiped is a unique linear combination of the primaries in the originating vertex, and the three edge primaries. This article proves that there exists a dissection such that these linear combinations are minimal-energy control sequences. In the generic case, this dissection is unique. An algorithm for a minimal-energy dissection is presented, along with an example.

The impact of chemotherapy dose intensity and supportive care on the risk of febrile neutropenia in patients with early stage breast cancer: a prospective cohort study.

BackgroundFebrile neutropenia (FN) is a major dose-limiting toxicity of cancer chemotherapy resulting in considerable morbidity, mortality, and cost. This study evaluated the time course of neutropenic events and patterns of supportive care interventions in patients receiving chemotherapy for early-stage breast cancer treated in oncology community practices.MethodsA prospective cohort study of adult cancer patients initiating a new chemotherapy regimen was conducted at 115 US sites. Toxicity associated with chemotherapy including neutropenic and infectious complications was recorded over four cycles. Clinical interventions were recorded including reductions in chemotherapy dose intensity and use of supportive care measures.ResultsA total of 1,202 patients with stage I–III breast cancer were evaluated. The majority of neutropenic (116 of 196) and infection events (179 of 325) occurred in the initial cycle. A decrease in occurrence of FN and infection was observed in the subsequent cycles, along with an increase in utilization of colony stimulating factors (CSFs), antibiotics and reductions in chemotherapy dose intensity. The overall risk of FN in all patients was 16.3%. In patients who started treatment at or near full dose intensity, the FN risk reached 21.0% without primary CSF prophylaxis and it was 9.0% with prophylaxis. There was no significant difference in FN rates by menopausal or hormone receptors status.ConclusionsThe risk of neutropenic complications is greatest in the initial cycle when most patients receive full-dose chemotherapy. A decrease in neutropenic events during subsequent cycles is associated with reduced dose intensity or increased use of supportive care measures. However, the cumulative risk of FN remains high in patients with early-stage breast cancer receiving full dose chemotherapy without prophylactic measures.

ELECTRODEPOSITION OF ZnO NANOROD ARRAYS FOR APPLICATION IN PEROVSKITE BASED SOLAR CELLS

We report a low-cost, free-hole conductor methylammonium lead iodide CH3NH3PbI3 (perovskite)/ZnO nanorods (NR) heterojunction solar cell. ZnO nanorod arrays were obtained electrochemically onto transparent conducting oxide (fluor doped tin oxide, FTO) from an aqueous solution of zinc acetate. The ZnO NR were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and optical transmittance. Solar cell was fabricated forming the perovskite material onto the ZnO thin film. Spin coating of an equimolar mixture of CH3NH3I and PbI2 in γ-butyrolactone solution (perovskite precursor solution) leads to CH3NH3PbI3 formation on ZnO NR. A graphite-covered FTO/glass was used as a back contact. The photovoltaic performance of the solar cell was characterized at full sun intensity of 100 mW/cm2 obtaining a shortcircuit current of 1.5 mA/cm2, an open circuit voltage of 0.47 V and energy conversion efficiency of 0.16 %.

TH‐EF‐BRD‐01: Fluence Map Optimization Using a Voxel‐Based Reduced‐Order Constrained Optimization Model

Purpose:To develop a method for adaptively imposing dose constraints on individual voxels and structures in IMRT planning, such that a sequence of computationally tractable, low‐dimensional constrained optimization problems is solved that leads to plans satisfying dose‐volume and other clinical constraints.Methods:The previously proposed Reduced Order Constrained Optimization (ROCO) algorithm is applied to parameterize an IMRT problem by a small number of coefficients on learned principal components, instead of a large number of independent beamlet fluences. A sequence of constrained optimization problems is solved over the set of coefficients in which the importance of each voxel and structure is adaptively changed in the objective function. Instead of manually investigating good settings for these parameters, an adaptive gain scheduling rule based on control theory automatically adjusts the weights, quickly converging to a plan satisfying the clinical constraints. In particular, we apply a decentralized proportional‐integral controller that adjusts structure weights using dose‐volume constraint (DVC) violation feedback. We compare our method against a previous approach in which subsets of voxels were iteratively selected and hard‐constrained in an attempt to satisfy DVCs.Results:The technique was tested on five different non‐nodal prostate cases, each resulting in clinically acceptable plans in less than 2.5 minutes on average. The quality of plans is far superior to the alternate method, significantly reducing OARs doses while meeting PTV V95 goals.Conclusion:Compared to alternative optimization schemes in the full intensity space, the propose scheme offers fast convergence rate, demands significantly less memory resources and computational effort, which allows larger IMRT problems to be addressed.

Tight focus of light using micropolarizer and microlens.

Using a binary microlens of diameter 14 μm and focal length 532 nm (NA=0.997) in resist, we focus a 633 nm laser beam into a near-circular focal spot with dimensions (0.35 ± 0.02)λ and (0.38 ± 0.02)λ (λ is incident wavelength) at full width half-maximum intensity. The area of the focal spot is 0.105λ(2). The incident light is a mixture of linearly and radially polarized beams generated by reflecting a linearly polarized Gaussian beam at a 100 μm × 100 μm four-sector subwavelength diffractive optical microelement with a gold coating. The focusing of a linearly polarized laser beam (the other conditions being the same) is found to produce an elliptical focal spot measuring (0.40 ± 0.02)λ and (0.50 ± 0.02)λ. To our knowledge, this is the first implementation of subwavelength focusing of light using a pair of micro-optic elements (a binary microlens and a micropolarizer).

Effects of self-seeding and crystal post-selection on the quality of Monte Carlo-integrated SFX data.

Serial femtosecond crystallography (SFX) is an emerging method for data collection at free-electron lasers (FELs) in which single diffraction snapshots are taken from a large number of crystals. The partial intensities collected in this way are then combined in a scheme called Monte Carlo integration, which provides the full diffraction intensities. However, apart from having to perform this merging, the Monte Carlo integration must also average out all variations in crystal quality, crystal size, X-ray beam properties and other factors, necessitating data collection from thousands of crystals. Because the pulses provided by FELs running in the typical self-amplified spontaneous emission (SASE) mode of operation have very irregular, spiky spectra that vary strongly from pulse to pulse, it has been suggested that this is an important source of variation contributing to inaccuracies in the intensities, and that, by using monochromatic pulses produced through a process called self-seeding, fewer images might be needed for Monte Carlo integration to converge, resulting in more accurate data. This paper reports the results of two experiments performed at the Linac Coherent Light Source in which data collected in both SASE and self-seeded mode were compared. Importantly, no improvement attributable to the use of self-seeding was detected. In addition, other possible sources of variation that affect SFX data quality were investigated, such as crystal-to-crystal variations reflected in the unit-cell parameters; however, these factors were found to have no influence on data quality either. Possibly, there is another source of variation as yet undetected that affects SFX data quality much more than any of the factors investigated here.

Sex differences in perception of invisible facial expressions.

Previous research indicates that women are better at recognizing facial expressions than men. In the current study, we examined whether this female advantage in the processing of facial expressions also occurs at the unconscious level. In two studies, participants performed a simple detection task and a 4-AFC task while faces were rendered invisible by continuous flash suppression. When faces with full intensity expressions were suppressed, there was no significant sex difference in the time of breakup of suppression (Study 1). However, when suppressed faces depicted low intensity expressions, suppression broke up earlier in men than women, indicating that men may be more sensitive to facial features related to mild facial expressions (Study 2). The current findings suggest that the female advantage in processing of facial expressions is absent in unconscious processing of emotional information. The female advantage in facial expression processing may require conscious perception of faces.

Complications of Reduced Intensity Conditioning HSCT for XIAP Deficiency (Alloimmune Cytopenias and HLH) Successfully Managed With Donor Lymphocyte Infusion

X-linked inhibitor of apoptosis protein deficiency is a rare illness and although stem cell transplant is curative, full intensity conditioning is associated with high mortality rates. We describe a child with unusual complications associated with residual host lymphocytes following reduced intensity stem cell transplant. Recipient derived, donor directed, antigranulocyte antibodies led to life-threatening and prolonged neutropenia and residual recipient lymphocytes reestablished hemophagocytic lymphohistiocytosis after withdrawal of immune suppression despite high levels of whole blood chimerism. Hemophagocytic lymphohistiocytosis was abolished following specific improvement in donor T-cell chimerism after donor lymphocyte infusions, and alloimmune cytopenias were no longer evident.

Duration and intensity of shade differentially affects mycorrhizal growth- and phosphorus uptake responses of Medicago truncatula.

Plant and fungal partners in arbuscular mycorrhizal symbiosis trade mineral nutrients for carbon, with the outcome of this relationship for plant growth and nutrition being highly context-dependent and changing with the availability of resources as well as with the specific requirements of the different partners. Here we studied how the model legume Medicago truncatula, inoculated or not with a mycorrhizal fungus Rhizophagus irregularis, responded to a gradient of light intensities applied over different periods of time, in terms of growth, phosphorus nutrition and the levels of root colonization by the mycorrhizal fungus. Short-term (6 d) shading, depending on its intensity, resulted in a rapid decline of phosphorus uptake to the shoots of mycorrhizal plants and simultaneous accumulation of phosphorus in the roots (most likely in the fungal tissues), as compared to the non-mycorrhizal controls. There was, however, no significant change in the levels of mycorrhizal colonization of roots due to short-term shading. Long-term (38 d) shading, depending on its intensity, provoked a multitude of plant compensatory mechanisms, which were further boosted by the mycorrhizal symbiosis. Mycorrhizal growth- and phosphorus uptake benefits, however, vanished at 10% of the full light intensity applied over a long-term. Levels of root colonization by the mycorrhizal fungus were significantly reduced by long-term shading. Our results indicate that even short periods of shade could have important consequences for the functioning of mycorrhizal symbiosis in terms of phosphorus transfer between the fungus and the plants, without any apparent changes in root colonization parameters or mycorrhizal growth response, and call for more focused research on temporal dynamics of mycorrhizal functioning under changing environmental conditions.

Umbilical Cord Blood Transplantation Conditioned without Serotherapy Is an Excellent Curative Alternative for Pediatric Non-Malignant Diseases

Stem cell transplantation for patients with non-malignant disorders is often challenging, with frequent failure to engraft. In the absence of an HLA-identical source, there is no consensus about the best alternative hemopoietic stem cell donor for patients who lack a matched sibling. Although cord blood transplant has been a recent option for these patients, an increased risk of viral infections and the potential for failed engraftment have remained problematic and associated with significant mortality. We therefore studied 25 children who underwent UCBT transplant at our institution for non-malignant disorders between 2007 and 2014. Their median age was 8 months (range, 2–66 months) an their diagnoses were: SCID (n=17), IPEX (n=2), LAD (n=1), Wiskott-Aldrich syndrome (n=1), Krabbe (n=1), mannosidosis (n=1), HLH (n=1), and Diamond-Blackfan anemia (n=1). Five patients had persistent viral infections prior to transplant: RSV (n=2), Parainfluenza 3 (n=1), VZV (n=1) and Norovirus (n=1), and 7 (30%) patients had required mechanical ventilation prior to transplantation. Eight of 25 patients were 6/6 HLA antigen matched with their cord stem cell donor, and 17 were one HLA antigen mismatched. All patients participated in a prospective trial consisting of myeloablative conditioning using busulfan, cyclophosphamide and fludarabine without the use of serotherapy. The median total nucleated cell dose in the transplant was 10x107 TNC/kg (range, 5.9–25.4). The median time to neutrophil recovery was 19 days (range,8-30) and the median time to platelet recovery was 38 days (range, 26-127). All but one evaluable patient achieved full donor chimerism (defined as > 95% donor cells in peripheral blood) by day +42. The exception was a patient with Krabbe’s disease who is nonetheless 60% donor chimeric at 6 months post-transplant with normalization of enzyme levels. No severe aGVHD or cGVHD has occurred and only one patient developed grade II aGVHD (skin). All except the patient with HLH (who died of multiorgan failure) are alive with a median follow up of 2 years (range, 10 days–5 years) and a 3-yr OS by Kaplan Meier analysis of 96% (95%CI: 73%-99%). All patients with viral infections at the time of transplant cleared the infection at a median time of 51 days (range, 44-54). ELISPOT analyses of peripheral blood at the time that infections responded showed significant T cell responses against the pertinent viruses. All evaluable patients have normalization of their immune or metabolic defect including adequate B cell function in SCID patients. Hence, UCBT after full intensity conditioning without serotherapy for pediatric non-malignant diseases can produce rapid functional engraftment and immune-reconstitution in the absence of significant GVHD, leading to excellent overall survival.

Influence of Light Intensity on the Yield and Quality of Houttuynia cordata

The contents of major nutrient components, and the composition and contents of medicinal substances were examined in Houttuynia cordata cultivated under field conditions and treated with natural light at full intensity, 40% intensity, and 20% intensity from sprouting to harvesting. The results indicated that the yield of the aboveground portion per unit area was highest at a 40% intensity and lowest at 20% intensity. The yield of the underground portion per unit area was highest under full intensity and lowest at a 20% intensity. As light intensity was reduced, protein and water content increased, while the contents of soluble sugar and fat, the contents of volatile oils both the aboveground and underground portion decreased. The total flavonoid content in both the aboveground and underground portions decreased with diminishing light intensity, but the composition of these flavonoids was hardly affected. In summary, although proper shading can increase the yield and the contents of some nutrients in H. cordata, this treatment reduces the net contents of medicinal components such as volatile oils and flavonoids, as well as the contents of active components. Therefore, it is necessary to provide sufficient light when growing H. cordata for medicinal and functional food purposes, but the crop may be treated with appropriate shading or intercropped when grown as food.

In vivo tracking of phosphoinositides in Drosophila photoreceptors.

ABSTRACTIn order to monitor phosphoinositide turnover during phospholipase C (PLC)-mediated Drosophila phototransduction, fluorescently tagged lipid probes were expressed in photoreceptors and imaged both in dissociated cells, and in eyes of intact living flies. Of six probes tested, TbR332H (a mutant of the Tubby protein pleckstrin homology domain) was judged the best reporter for phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2], and the P4M domain from Legionella SidM for phosphatidylinositol 4-phosphate (PtdIns4P). Using accurately calibrated illumination, we found that only ∼50% of PtdIns(4,5)P2 and very little PtdIns4P were depleted by full daylight intensities in wild-type flies, but both were severely depleted by ∼100-fold dimmer intensities in mutants lacking Ca2+-permeable transient receptor potential (TRP) channels or protein kinase C (PKC). Resynthesis of PtdIns4P (t½ ∼12 s) was faster than PtdIns(4,5)P2 (t½ ∼40 s), but both were greatly slowed in mutants of DAG kinase (rdgA) or PtdIns transfer protein (rdgB). The results indicate that Ca2+- and PKC-dependent inhibition of PLC is required for enabling photoreceptors to maintain phosphoinositide levels despite high rates of hydrolysis by PLC, and suggest that phosphorylation of PtdIns4P to PtdIns(4,5)P2 is the rate-limiting step of the cycle.

VO₂ kinetics and metabolic contributions during full and upper body extreme swimming intensity.

Our purpose was to characterize the oxygen uptake ([Formula: see text]) kinetics, assess the energy systems contributions and determine the energy cost when swimming front crawl at extreme intensity. Complementarily, we compared swimming full body with upper body only. Seventeen swimmers performed a 100 m maximal front crawl in two conditions: once swimming with full body and other using only the upper propulsive segments. The [Formula: see text] was continuously measured using a telemetric portable gas analyser (connected to a respiratory snorkel), and the capillary blood samples for lactate concentration analysis were collected. A sudden increase in [Formula: see text] in the beginning of exercise, which continuously rose until the end of the bout (time: 63.82 ± 3.38 s; [Formula: see text]: 56.07 ± 5.19 ml min(-1) kg(-1); [Formula: see text] amplitude: 41.88 ± 4.74 ml min(-1) kg(-1); time constant: 12.73 ± 3.09 s), was observed. Aerobic, anaerobic lactic and alactic pathways were estimated and accounted for 43.4, 33.1 and 23.5 % of energy contribution and 1.16 ± 0.10 kJ m(-1) was the energy cost. Complementarily, the absence of lower limbs lead to a longer time to cover 100 m (71.96 ± 5.13 s), slower [Formula: see text] kinetics, lower aerobic and anaerobic (lactic and alactic) energy production and lower energy cost. Despite the short duration of the event, the aerobic energy contribution covers about 50 % of total metabolic energy liberation, highlighting that both aerobic and anaerobic energy processes should be developed to improve the 100 m swimming performance. Lower limbs action provided an important contribution in the energy availability in working muscles being advised its full use in this short duration and very high-intensity event.

Synergy of Unrelated Donor and Full Intensity Conditioning Breaks the Control of Graft Versus Host Disease By Alemtuzumab

Many variables influence the risk of graft versus host disease following hematopoietic stem cell transplantation. Comparison between preparative regimens is hampered by the use of many different combinations of chemotherapy and radiotherapy, varying intensity of conditioning, use of T cell depletion and donors who are either siblings or unrelated volunteers. Many reduced intensity regimens also incorporate enhanced GVHD prophylaxis with in vivo T cell depletion. Here we describe a cohort of patients prepared in a modular fashion with either reduced or full intensity conditioning combined with a uniform GVHD prophylaxis regimen for all transplants with sibling donors (alemtuzumab 30mg) and for all with unrelated donors (UD; alemtuzumab 60mg). Thus it was possible to dissect independently the effect of conditioning intensity and sibling or UD type upon GVHD risk in this settig of in vivo T cell depletion.Patients and analysis: the study was a retrospective analysis of 258 sequential transplants performed in adults with hematological malignancy between September 2005 and September 2013 at a single UK institution. Reduced intensity conditioning (n = 221) included fludarabine 150mg/m2 plus melphalan 140mg/m2 or fludarabine 150mg/m2 plus busulfan 9.6mg/kg. Full intensity transplants (n = 37) received 12Gy TBI plus melphalan 140mg/m2, 12Gy TBI plus cyclophosphamide 120mg/kg, or busulfan 16mg/kg plus cyclophosphamide 120mg/kg. All patients with sibling donors received 30mg alemtuzumab and those with UD received a 60mg of alemtuzumab. UD matching was similar in both reduced intensity and full intensity cohorts (92.2% and 86.5% 10/10 matches, respectively) but patients receiving reduced intensity were older than those receiving full intensity conditioning (median age 51 vs 31; p < 0.001). Outcome was analyzed according to EBMT guidelines. Relapse, non-relapse mortality and cGVHD were treated as competing risks and analysed as cumulative incidence.Outcome: the incidence of acute GVHD grades I-IV was comparable between reduced intensity and full intensity sibling transplants (45% vs 45%; p = NS) indicating a lack of effect of conditioning intensity upon GVHD risk in this setting. There was a slight increase in the risk of GVHD between reduced intensity UD compared with reduced intensity sibling donor transplants (57% vs 45%; p = NS) but a marked synergistic increase between UD transplants performed with full intensity compared with reduced intensity conditioning (100% vs 57%; p = < 0.001). The incidence of grades III-IV acute GVHD was also higher in full intensity UD transplants (16%) compared with reduced intensity UD transplants (5%). The incidence of chronic GVHD was also highest in full intensity UD transplants but both conditioning intensity and UD contributed in an additive manner: the rate of chronic GVHD progressed from 33% to 44% in reduced intensity and full intensity sibling transplants respectively and from 57% to 75% for reduced and full intensity UD transplants, respectively. Two year overall survival was comparable in all groups, ranging from 55% to 70%. In keeping with the higher rates of acute GVHD in full intensity transplants performed with UD, this group experienced the lowest relapse risk (15% vs 29% for all the other groups combined; p = 0.04) but the highest non-relapse mortality, reaching 41% at 2 years compared with 28% for all the other groups combined (p = 0.08).Conclusion: these results show that alemtuzumab provides good protection from acute GVHD in reduced intensity transplantation from sibling and UD. In sibling transplants given identical GVHD prophylaxis, full intensity conditioning does not increase the risk of GVHD. In contrast, a slight increase in GVHD risk with UD transplants seen with reduced intensity conditioning, is amplified in a synergistic manner by full intensity conditioning. This is associated with a high non-relapse mortality, even though the median age of full intensity patients is more than 20 years younger than those receiving reduced intensity conditioning. DisclosuresNo relevant conflicts of interest to declare.

Therapy-Related Acute Lymphoblastic Leukemia: Cytogenetic Features and Hematopoietic Cell Transplantation Outcome

The clinical and pathologic characteristics and treatment outcome of therapy-related acute lymphoblastic leukemia (t-ALL) remains less defined compared to therapy-related acute myeloid leukemia. Although MLL rearrangement is the most characteristic genetic abnormality associated with t-ALL, other chromosomal alterations have been described.We examined the pathologic features and treatment outcome of a cohort of t-ALL patients who were undergoing allogeneic hematopoietic cell transplantation (HCT) in order to better define the cytogenetic profile of t-ALL, and to determine the outcome of t-ALL with allogeneic HCT. We reviewed all consecutive cases of adult ALL that had undergone allogeneic HCT at our institution between 1998 and 2014. Data on previous malignancy, chemotherapy, radiation, cytogenetic abnormalities and survival were collected and analyzed.We identified 28 cases of t-ALL who had history of chemotherapy and/or radiation prior to ALL diagnosis and subsequently undergone allogeneic HCT at our institution. The median age was 48 years (range 29-61), and 57% of patients were female. The most common prior diagnosis was breast cancer (n=9), followed by multiple myeloma (n=4), sarcoma (n=4), thyroid cancer/disease (n=4), lymphoma (n=3), germ cell tumor (n=2, including a case of combined germ cell and CLL), melanoma (n=1), and colon cancer (n=1). The median interval from initial diagnosis of malignancy to diagnosis of t-ALL was 7.3 years (range; 0.9-50.7). Thirty-nine percent had prior combination of chemotherapy and radiation therapy, 32% had prior radiotherapy alone and 29% had prior chemotherapy alone. Four patients had undergone autologous-HCT prior to t-ALL onset. All cases had B-cell phenotype. Median initial WBC was 8 X 109/L (range 1.2-323). Interestingly, in our cohort the most common cytogenetic abnormality was t(9;22) [Philadelphia chromosome] (39%), and followed by MLL rearrangement (25%). The median interval from diagnosis of previous malignancy to ALL diagnosis was 9.3 years for Ph+ ALL, 2.1 years for MLL-rearranged ALL, and 7.9 years for other cytogenetic types of t-ALL. The median initial WBC on presentation was 8 X 109/L for Ph+ ALL, 17 X 109/L for MLL-rearranged ALL, and 8 X 109/L for other cytogenetic types of t-ALL. Disease status at the time of HCT was as follows: 20 patients were in CR1, 2 were in CR2, 3 were in first relapse and another 3 after induction failure. Conditioning regimen was full intensity in 16 patients and reduced intensity in 12. Four-year Leukemia-free survival (LFS) and overall survival (OS) for the whole cohort were 46% and 49%, respectively. The 4-year LFS and OS for MLL-rearranged cases, Ph+ cases and other cytogenetic types were (62% vs. 43% vs. 40%, p=0.68) and (60% vs. 56% vs. 35%, p=0.71), respectively. In this cohort, only one patient relapsed with the original disease (CLL) after allogeneic HCT. The 100 days non-relapse mortality for evaluable patients was 8%.Ph+ t-ALL is an under recognized subtype of t-ALL and appears to be at least as common as MLL rearrangement among t-ALL. The HCT outcome of t-ALL appears to be similar to de novo ALL. DisclosuresNo relevant conflicts of interest to declare.