How I treat myelofibrosis Cervantes, Francisco
Blood,
10/2014, Letnik:
124, Številka:
17
Journal Article
Recenzirano
Odprti dostop
Myelofibrosis (MF) is a BCR-ABL1–negative myeloproliferative neoplasm characterized by clonal myeloproliferation, dysregulated kinase signaling, and release of abnormal cytokines. In recent years, ...important progress has been made in the knowledge of the molecular biology and the prognostic assessment of MF. Conventional treatment has limited impact on the patients' survival; it includes a wait-and-see approach for asymptomatic patients, erythropoiesis-stimulating agents, androgens, or immunomodulatory agents for anemia, cytoreductive drugs such as hydroxyurea for the splenomegaly and constitutional symptoms, and splenectomy or radiotherapy in selected patients. The discovery of the Janus kinase (JAK)2 mutation triggered the development of molecular targeted therapy of MF. The JAK inhibitors are effective in both JAK2-positive and JAK2-negative MF; one of them, ruxolitinib, is the current best available therapy for MF splenomegaly and constitutional symptoms. However, although ruxolitinib has changed the therapeutic scenario of MF, there is no clear indication of a disease-modifying effect. Allogeneic stem cell transplantation remains the only curative therapy of MF, but due to its associated morbidity and mortality, it is usually restricted to eligible high- and intermediate-2–risk MF patients. To improve current therapeutic results, the combination of JAK inhibitors with other agents is currently being tested, and newer drugs are being investigated.
Background: Obesity has been on the rise for the past several decades, which is associated with increased risk for comorbidities and severe consequences to the individual. In the Mexican American ...community, obesity has become a serious problem in children. The COVID-19 lockdown order issued in February 2020 caused further challenges for children to engage in regular physical activity.
Objective: To determine if the COVID-19 lockdown impacted the weight of 95% Medicaid-insured Mexican American children at a pediatric clinic in South Texas.
Design and Methods: We identified 417 new patients from March 2019 to February 2020 (with exclusion of 104 newborns) and followed them until December 2021. Height and weight were measured to estimate Body Mass Index (BMI) . The percentage of overweight or obese (OW/OB) children was calculated at the first and last visit.
Results: We had a total of 346 children at the end of the study. The average stature of the whole group was at the 48th percentile with 60% of the children at or below the 50th percentile based on CDC growth charts. Boys increased BMI from the 62.7th to 71.8th percentile (p<0.01) and girls increased from the 60th to the 70th percentile (p<0.02) . The distribution of BMI of the whole group indicated that 34.5% of children were OW/OB on the first visit and 49% were OW/OB at the last visit.
Conclusion (s) : Our study exemplifies that the lockdown during the COVID-19 pandemic, which was associated with decreased physical activity, increased the BMI of children and increased associated comorbidities based on lab values. We have shown in previous studies that when BMI is in the OW/OB category, children have increased blood pressure, decreased high density lipoproteins, elevated liver enzymes, increased insulin resistance, larger kidneys, and fatty liver. These indicators place children at a higher risk for early development of hypertension, renal function decline, diabetes, and cardiovascular disease.
Disclosure
F. J. Cervantes: None.
Humic substances (HS) constitute a highly transformed fraction of natural organic matter (NOM) with a heterogeneous structure, which is rich in electron-transferring functional moieties. Because of ...this feature, HS display a versatile reactivity with a diversity of environmentally relevant organic and inorganic compounds either by abiotic or microbial processes. Consequently, extensive research has been conducted related to the potential of HS to drive relevant processes in bio-engineered systems, as well as in the biogeochemical cycling of key elements in natural environments. Nevertheless, the increase in the number of reports examining the relationship between HS and the microorganisms related to the production and consumption of greenhouse gases (GHG), the main drivers of global warming, has just emerged in the last years. In this paper, we discuss the importance of HS, and their analogous redox-active organic molecules (RAOM), on controlling the emission of three of the most relevant GHG due to their tight relationship with microbial activity, their abundance on the Earth's atmosphere, and their important global warming potentials: carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O). The current knowledge gaps concerning the microbial component, on-site occurrence, and environmental constraints affecting these HS-mediated processes are provided. Furthermore, strategies involving the metabolic traits that GHG-consuming/HS-reducing and –oxidizing microbes display for the development of environmental engineered processes are also discussed.
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•Microbial processes mediated by HS suppressing GHG emissions are reviewed.•Environmental relevance of redox-active organic molecules (RAOM) is discussed.•Key microbiological and thermodynamic aspects are presented.•Research directions and plausible technologies are proposed.
Selective attentional biases arising from one sensory modality manifest in others. The effects of visuospatial attention, important in visual object perception, are unclear in the auditory domain ...during audiovisual (AV) scene processing. We investigate temporal and spatial factors that underlie such transfer neurally. Auditory encoding of random tone pips in AV scenes was addressed via a temporal response function model (TRF) of participants' electroencephalogram (N = 30). The spatially uninformative pips were associated with spatially distributed visual contrast reversals (“flips”), through asynchronous probabilistic AV temporal onset distributions. Participants deployed visuospatial selection on these AV stimuli to perform a task. A late (~300 ms) cross‐modal influence over the neural representation of pips was found in the original and a replication study (N = 21). Transfer depended on selected visual input being (i) presented during or shortly after a related sound, in relatively limited temporal distributions (<165 ms); (ii) positioned across limited (1:4) visual foreground to background ratios. Neural encoding of auditory input, as a function of visual input, was largest at visual foreground quadrant sectors and lowest at locations opposite to the target. The results indicate that ongoing neural representations of sounds incorporate visuospatial attributes for auditory stream segregation, as cross‐modal transfer conveys information that specifies the identity of multisensory signals. A potential mechanism is by enhancing or recalibrating the tuning properties of the auditory populations that represent them as objects. The results account for the dynamic evolution under visual attention of multisensory integration, specifying critical latencies at which relevant cortical networks operate.
Spatial selection guides object representation in vision. This EEG study demonstrates that visuospatial attention reshapes the neural encoding of auditory elements in competing audiovisual (AV) stimuli. Cross‐modally transferred visuospatial biases reformat the representation of likely on‐target sounds. The association can be shown by two key distributional properties: AV precision and foreground size.
After nearly 11 years of follow-up, long-term administration of imatinib was shown to be associated with prolonged control of chronic myeloid leukemia and no cumulative or late toxic effects have ...emerged.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that is characterized by the Philadelphia (Ph) chromosome and driven by its product, the BCR-ABL1 tyrosine kinase.
1
In 2001, imatinib was introduced as a BCR-ABL1 tyrosine kinase inhibitor and was approved for the treatment of CML on the basis of a high level of activity in phase 2 studies.
2
Early results from the phase 3 International Randomized Study of Interferon and STI571 (IRIS) showed that imatinib at a dose of 400 mg once daily was more active and was associated with fewer side effects than interferon alfa plus cytarabine in patients with . . .
This document updates the recommendations on the management of Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) published in 2011 by the European LeukemiaNet (ELN) ...consortium. Recommendations were produced by multiple-step formalized procedures of group discussion. A critical appraisal of evidence by using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) methodology was performed in the areas where at least one randomized clinical trial was published. Seven randomized controlled trials provided the evidence base; earlier phase trials also informed recommendation development. Key differences from the 2011 diagnostic recommendations included: lower threshold values for hemoglobin and hematocrit and bone marrow examination for diagnosis of polycythemia vera (PV), according to the revised WHO criteria; the search for complementary clonal markers, such as ASXL1, EZH2, IDH1/IDH2, and SRSF2 for the diagnosis of myelofibrosis (MF) in patients who test negative for JAK2V617, CALR or MPL driver mutations. Regarding key differences of therapy recommendations, both recombinant interferon alpha and the JAK1/JAK2 inhibitor ruxolitinib are recommended as second-line therapies for PV patients who are intolerant or have inadequate response to hydroxyurea. Ruxolitinib is recommended as first-line approach for MF-associated splenomegaly in patients with intermediate-2 or high-risk disease; in case of intermediate-1 disease, ruxolitinib is recommended in highly symptomatic splenomegaly. Allogeneic stem cell transplantation is recommended for transplant-eligible MF patients with high or intermediate-2 risk score. Allogeneic stem cell transplantation is also recommended for transplant-eligible MF patients with intermediate-1 risk score who present with either refractory, transfusion-dependent anemia, blasts in peripheral blood > 2%, adverse cytogenetics, or high-risk mutations. In these situations, the transplant procedure should be performed in a controlled setting.
During the last two decades, extensive research has explored the catalytic effects of different organic molecules with redox mediating properties on the anaerobic (bio)transformation of a wide ...variety of organic and inorganic compounds. The accumulated evidence points at a major role of electron shuttles in the redox conversion of several distinct contaminants, both by chemical and biological mechanisms. Many microorganisms are capable of reducing redox mediators linked to the anaerobic oxidation of organic and inorganic substrates. Electron shuttles can also be chemically reduced by electron donors commonly found in anaerobic environments (e.g. sulfide and ferrous iron). Reduced electron shuttles can transfer electrons to several distinct electron-withdrawing compounds, such as azo dyes, polyhalogenated compounds, nitroaromatics and oxidized metalloids, among others. Moreover, reduced molecules with redox properties can support the microbial reduction of electron acceptors, such as nitrate, arsenate and perchlorate. The aim of this review paper is to summarize the results of reductive (bio)transformation processes catalyzed by electron shuttles and to indicate which aspects should be further investigated to enhance the applicability of redox mediators on the (bio)transformation of contaminants.
Antimony, extensively used in energy applications, poses toxicity and contamination concerns, especially in anaerobic environments where its impact on microbial activity is poorly understood. ...Emerging remedies, like biochar, show promise in soil and water treatment. This study investigates biochar's influence on methanogenic activity under Sb(V) and Sb(III) stress using anaerobic sludge as inoculum and lactate as the carbon source. Sb(III) and Sb(V) were introduced at varied concentrations (5-80 mg/L), with or without biochar, monitoring changes in biogas production, pH, Sb, and lactate levels over time. Experiments with Sb(V) also involved calculating mass balance and electron distribution. Results showcased the following significant enhancements: biochar notably improved COD removal and biogas production in Sb(III) spiked conditions, up to 5-fold and 2-fold increases, respectively. Sb(III) removal reached up to 99% with biochar, while in high Sb(V) concentrations, biochar reduced the adverse effect on biogas production by 96%. Adsorption capacities favored biomass (60.96 mg Sb(III)/gVSS, and 22.4 mg Sb(V)/gVSS) over biochar (3.33 mg Sb(III)/g, and 1.61 mg Sb(V)/g) for both Sb species. This study underscores biochar's potential to mitigate metalloid impact on methanogenic activity while aiding Sb removal from liquid phase, suggesting promising implications for remediation and methane production enhancement strategies.
•Two subtropical reservoirs with contrasting trophic states were characterized.•Methane, oxygen, and carbon dioxide were measured with high resolution methods.•Several parameters related to carbon ...cycling were determined over three seasons.•These parameters were regrouped in a single graphical representation.•Eutrophication caused a complete redistribution of the major bioprocesses involved.
The impact of cultural eutrophication on carbon cycling in subtropical reservoirs was assessed using high-resolution measurements of dissolved gas concentration, atmospheric exchange, and uptake/production rates of methane, carbon dioxide, and oxygen. Seasonal measurements were performed in two reservoirs that pertain to the same hydrological basin but are drastically different in terms of allochthonous carbon input. These results were used to feed a mass balance model, from which a large number of overall parameters were determined to explicitly describe the dynamics and spatial attributes of the carbon cycle in the reservoirs. A single graphical representation of each reservoir was created to facilitate an overall appraisal of the carbon cycle. The impact of cultural eutrophication was profound and resulted in a complete redistribution of how the various bioprocesses participated in the methane, carbon dioxide, and oxygen cycles. Among several identified impacts of eutrophication, it was observed that while eutrophication triggered increased methane production, this effect was followed by a similar increase in methane emissions and methanotrophic rates, while gross primary production was depleted.
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Wetlands constitute the main natural source of methane on Earth due to their high content of natural organic matter (NOM), but key drivers, such as electron acceptors, supporting methanotrophic ...activities in these habitats are poorly understood. We performed anoxic incubations using freshly collected sediment, along with water samples harvested from a tropical wetland, amended with
C-methane (0.67 atm) to test the capacity of its microbial community to perform anaerobic oxidation of methane (AOM) linked to the reduction of the humic fraction of its NOM. Collected evidence demonstrates that electron-accepting functional groups (e.g., quinones) present in NOM fueled AOM by serving as a terminal electron acceptor. Indeed, while sulfate reduction was the predominant process, accounting for up to 42.5% of the AOM activities, the microbial reduction of NOM concomitantly occurred. Furthermore, enrichment of wetland sediment with external NOM provided a complementary electron-accepting capacity, of which reduction accounted for ∼100 nmol
CH
oxidized · cm
· day
Spectroscopic evidence showed that quinone moieties were heterogeneously distributed in the wetland sediment, and their reduction occurred during the course of AOM. Moreover, an enrichment derived from wetland sediments performing AOM linked to NOM reduction stoichiometrically oxidized methane coupled to the reduction of the humic analogue anthraquinone-2,6-disulfonate. Microbial populations potentially involved in AOM coupled to microbial reduction of NOM were dominated by divergent biota from putative AOM-associated archaea. We estimate that this microbial process potentially contributes to the suppression of up to 114 teragrams (Tg) of CH
· year
in coastal wetlands and more than 1,300 Tg · year
, considering the global wetland area.
The identification of key processes governing methane emissions from natural systems is of major importance considering the global warming effects triggered by this greenhouse gas. Anaerobic oxidation of methane (AOM) coupled to the microbial reduction of distinct electron acceptors plays a pivotal role in mitigating methane emissions from ecosystems. Given their high organic content, wetlands constitute the largest natural source of atmospheric methane. Nevertheless, processes controlling methane emissions in these environments are poorly understood. Here, we provide tracer analysis with
CH
and spectroscopic evidence revealing that AOM linked to the microbial reduction of redox functional groups in natural organic matter (NOM) prevails in a tropical wetland. We suggest that microbial reduction of NOM may largely contribute to the suppression of methane emissions from tropical wetlands. This is a novel avenue within the carbon cycle in which slowly decaying NOM (e.g., humic fraction) in organotrophic environments fuels AOM by serving as a terminal electron acceptor.
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