Search results for: Eduardo Álvarez

Authors: B. R. Campomanes-Alvarez, P. Quiros, B. Fernandez

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Automatic Speech Recognition (ASR) is a machine-based process of decoding and transcribing oral speech. A typical ASR system receives acoustic input from a speaker or an audio file, analyzes it using algorithms, and produces an output in the form of a text. Some speech recognition systems use Hidden Markov Models (HMMs) to deal with the temporal variability of speech and Gaussian Mixture Models (GMMs) to determine how well each state of each HMM fits a short window of frames of coefficients that represents the acoustic input. Another way to evaluate the fit is to use a feed-forward neural network that takes several frames of coefficients as input and produces posterior probabilities over HMM states as output. Deep neural networks (DNNs) that have many hidden layers and are trained using new methods have been shown to outperform GMMs on a variety of speech recognition systems. Acoustic models for state-of-the-art ASR systems are usually training on massive amounts of data. However, audio files with their corresponding transcriptions can be difficult to obtain, especially in the Spanish language. Hence, in the case of these low-resource scenarios, building an ASR model is considered as a complex task due to the lack of labeled data, resulting in an under-trained system. Semi-supervised learning approaches arise as necessary tasks given the high cost of transcribing audio data. The main goal of this proposal is to develop a procedure based on acoustic semi-supervised learning for Spanish ASR systems by using DNNs. This semi-supervised learning approach consists of: (a) Training a seed ASR model with a DNN using a set of audios and their respective transcriptions. A DNN with a one-hidden-layer network was initialized; increasing the number of hidden layers in training, to a five. A refinement, which consisted of the weight matrix plus bias term and a Stochastic Gradient Descent (SGD) training were also performed. The objective function was the cross-entropy criterion. (b) Decoding/testing a set of unlabeled data with the obtained seed model. (c) Selecting a suitable subset of the validated data to retrain the seed model, thereby improving its performance on the target test set. To choose the most precise transcriptions, three confidence scores or metrics, regarding the lattice concept (based on the graph cost, the acoustic cost and a combination of both), was performed as selection technique. The performance of the ASR system will be calculated by means of the Word Error Rate (WER). The test dataset was renewed in order to extract the new transcriptions added to the training dataset. Some experiments were carried out in order to select the best ASR results. A comparison between a GMM-based model without retraining and the DNN proposed system was also made under the same conditions. Results showed that the semi-supervised ASR-model based on DNNs outperformed the GMM-model, in terms of WER, in all tested cases. The best result obtained an improvement of 6% relative WER. Hence, these promising results suggest that the proposed technique could be suitable for building ASR models in low-resource environments.

Keywords: automatic speech recognition, deep neural networks, machine learning, semi-supervised learning

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Authors: Andre Pastori D'Aurea, Lauriston Bertelli Feranades, Luis Eduardo Ferreira, Leandro Dias Pinto, Fabiana Ayumi Shiozaki

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The aim of this study was to improve the production of beef cattle on tropical pasture without harming this environment. On tropical pastures, cattle's live weight gain is lower than feedlot, and forage production is seasonable, changing from season to season. Thus, concerned with sustainable livestock production, the Premix Company has developed strategies to improve the production of beef cattle on tropical pasture to ensure sustainability of welfare and production. There are two important principles in this productivity system: 1) increase individual gains with use of better supplementation and 2) increase the productivity units with better forage quality like corn silage or other forms of forage conservations, actually used only in winter, and adding natural additives in the diet. This production system was applied from June 2017 to May 2018 in the Research Center of Premix Company, Patrocínio Paulista, São Paulo State, Brazil. The area used had 9 hectares of pasture of Brachiaria brizantha. 36 steers Nellore were evaluated for one year. The initial weight was 253 kg. The parameters used were daily average gain and gain per area. This indicated the corrections to be made and helped design future fertilization. In this case, we fertilized the pasture with 30 kg of nitrogen per animal divided into two parts. The diet was pasture and protein-energy supplements (0.4% of live weight). The supplement used was added with natural additive Fator P® – Premix Company). Fator P® is an additive composed by amino acids (lysine, methionine and tyrosine, 16400, 2980 and 3000 mg.kg-1 respectively), minerals, probiotics (Saccharomyces cerevisiae, 7 x 10E8 CFU.kg-1) and essential fatty acids (linoleic and oleic acids, 108.9 and 99g.kg-1 respectively). Due to seasonal changes, in the winter we supplemented the diet by increasing the offer of forage, supplementing with maize silage. It was offered 1% of live weight in silage corn and 0.4% of the live weight in protein-energetic supplements with additive Fator P ®. At the end of the period, the productivity was calculated by summing the individual gains for the area used. The average daily gain of the animals were 693 grams per day and was produced 1.005 kg /hectare/year. This production is about 8 times higher than the average of Brazilian meat national production. To succeed in this project, it is necessary to increase the gains per area, so it is necessary to increase the capacity per area. Pasture management is very important to the project's success because the dietary decisions were taken from the quantity and quality of the forage. We, therefore, recommend the use of animals in the growth phase because the response to supplementation is greater in that phase and we can allocate more animals per area. This system's carbon footprint reduces emissions by 61.2 percent compared to the Brazilian average. This beef cattle production system can be efficient and environmentally friendly to the natural. Another point is that bovines will benefit from their natural environment without competing or having an impact on human food production.

Keywords: cattle production, environment, pasture, sustainability

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Authors: Pablo Oteiza, Ricardo Alvarez, Mehrdad Pirnia, Fuat Can

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To effectively combat climate change, many countries around the world have committed to a decarbonisation of their electricity, along with promoting a large-scale integration of renewable energy sources (RES). While this trend represents a unique opportunity to effectively combat climate change, achieving a sound and cost-efficient energy transition towards low-carbon power systems poses significant challenges for the multi-year Transmission Network Expansion Planning (TNEP) problem. The objective of the multi-year TNEP is to determine the necessary network infrastructure to supply the projected demand in a cost-efficient way, considering the evolution of the new generation mix, including the integration of RES. The rapid integration of large-scale RES increases the variability and uncertainty in the power system operation, which in turn increases short-term flexibility requirements. To meet these requirements, flexible generating technologies such as energy storage systems must be considered within the TNEP as well, along with proper models for capturing the operational challenges of future power systems. As a consequence, TNEP formulations are becoming more complex and difficult to solve, especially for its application in realistic-sized power system models. To meet these challenges, there is an increasing need for developing efficient algorithms capable of solving the TNEP problem with reasonable computational time and resources. In this regard, a promising research area is the use of artificial intelligence (AI) techniques for solving large-scale mixed-integer optimization problems, such as the TNEP. In particular, the use of AI along with mathematical optimization strategies based on decomposition has shown great potential. In this context, this paper presents an efficient algorithm for solving the multi-year TNEP problem. The algorithm combines AI techniques with Column Generation, a traditional decomposition-based mathematical optimization method. One of the challenges of using Column Generation for solving the TNEP problem is that the subproblems are of mixed-integer nature, and therefore solving them requires significant amounts of time and resources. Hence, in this proposal we solve a linearly relaxed version of the subproblems, and trained a binary classifier that determines the value of the binary variables, based on the results obtained from the linearized version. A key feature of the proposal is that we integrate the binary classifier into the optimization algorithm in such a way that the optimality of the solution can be guaranteed. The results of a study case based on the HRP 38-bus test system shows that the binary classifier has an accuracy above 97% for estimating the value of the binary variables. Since the linearly relaxed version of the subproblems can be solved with significantly less time than the integer programming counterpart, the integration of the binary classifier into the Column Generation algorithm allowed us to reduce the computational time required for solving the problem by 50%. The final version of this paper will contain a detailed description of the proposed algorithm, the AI-based binary classifier technique and its integration into the CG algorithm. To demonstrate the capabilities of the proposal, we evaluate the algorithm in case studies with different scenarios, as well as in other power system models.

Keywords: integer optimization, machine learning, mathematical decomposition, transmission planning

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Authors: L. R. Valencia Pérez, J. M. Peña Aguilar, A. Lamadrid Álvarez, A. Pastrana Palma, H. F. Valencia Pérez, M. Vivanco Vargas

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This work proposes a Cooperation-Competitive (Coopetitive) approach that allows coordinated work among the Secretary of Public Education (SEP), the Autonomous University of Querétaro (UAQ) and government funds from National Council for Science and Technology (CONACYT) or some other international organizations. To work on an overall knowledge transfer strategy with e-learning over the Cloud, where experts in junior high and high school education, working in multidisciplinary teams, perform analysis, evaluation, design, production, validation and knowledge transfer at large scale using a Cloud Computing platform. Allowing teachers and students to have all the information required to ensure a homologated nationally knowledge of topics such as mathematics, statistics, chemistry, history, ethics, civism, etc. This work will start with a pilot test in Spanish and initially in two regional dialects Otomí and Náhuatl. Otomí has more than 285,000 speaking indigenes in Queretaro and Mexico´s central region. Náhuatl is number one indigenous dialect spoken in Mexico with more than 1,550,000 indigenes. The phase one of the project takes into account negotiations with indigenous tribes from different regions, and the Information and Communication technologies to deliver the knowledge to the indigenous schools in their native dialect. The methodology includes the following main milestones: Identification of the indigenous areas where Otomí and Náhuatl are the spoken dialects, research with the SEP the location of actual indigenous schools, analysis and inventory or current schools conditions, negotiation with tribe chiefs, analysis of the technological communication requirements to reach the indigenous communities, identification and inventory of local teachers technology knowledge, selection of a pilot topic, analysis of actual student competence with traditional education system, identification of local translators, design of the e-learning platform, design of the multimedia resources and storage strategy for “Cloud Computing”, translation of the topic to both dialects, Indigenous teachers training, pilot test, course release, project follow up, analysis of student requirements for the new technological platform, definition of a new and improved proposal with greater reach in topics and regions. Importance of phase one of the project is multiple, it includes the proposal of a working technological scheme, focusing in the cultural impact in Mexico so that indigenous tribes can improve their knowledge about new forms of crop improvement, home storage technologies, proven home remedies for common diseases, ways of preparing foods containing major nutrients, disclose strengths and weaknesses of each region, communicating through cloud computing platforms offering regional products and opening communication spaces for inter-indigenous cultural exchange.

Keywords: Mexicans indigenous tribes, education, knowledge transfer, cloud computing, otomi, Náhuatl, language

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Authors: Jose A. Alvarez Aldegunde, Adrian Fernandez Sanchez, Matthew D. Menden, Bernardo Vila Rodriguez

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Up to five statistical pre-processings have been carried out considering the pollutant records of the stations present in Cartagena de Indias, Colombia, also taking into account the childhood asthma incidence surveys conducted in hospitals in the city by the Health Ministry of Colombia for this study. These pre-processings have consisted of different techniques such as the determination of the quality of data collection, determination of the quality of the registration network, identification and debugging of errors in data collection, completion of missing data and purified data, as well as the improvement of the time scale of records. The characterization of the quality of the data has been conducted by means of density analysis of the pollutant registration stations using ArcGis Software and through mass balance techniques, making it possible to determine inconsistencies in the records relating the registration data between stations following the linear regression. The results obtained in this process have highlighted the positive quality in the pollutant registration process. Consequently, debugging of errors has allowed us to identify certain data as statistically non-significant in the incidence and series of contamination. This data, together with certain missing records in the series recorded by the measuring stations, have been completed by statistical imputation equations. Following the application of these prior processes, the basic series of incidence data for respiratory disease and pollutant records have allowed the characterization of the influence of pollutants on respiratory diseases such as, for example, childhood asthma. This characterization has been carried out using statistical correlation methods, including visual correlation, simple linear regression correlation and spectral analysis with PAST Software which identifies maximum periodicity cycles and minimums under the formula of the Lomb periodgram. In relation to part of the results obtained, up to eleven maximums and minimums considered contemporary between the incidence records and the particles have been identified taking into account the visual comparison. The spectral analyses that have been performed on the incidence and the PM2.5 have returned a series of similar maximum periods in both registers, which are at a maximum during a period of one year and another every 25 days (0.9 and 0.07 years). The bivariate analysis has managed to characterize the variable "Daily Vehicular Flow" in the ninth position of importance of a total of 55 variables. However, the statistical correlation has not obtained a favorable result, having obtained a low value of the R2 coefficient. The series of analyses conducted has demonstrated the importance of the influence of pollutants such as PM2.5 in the development of childhood asthma in Cartagena. The quantification of the influence of the variables has been able to determine that there is a 56% probability of dependence between PM2.5 and childhood respiratory asthma in Cartagena. Considering this justification, the study could be completed through the application of the BenMap Software, throwing a series of spatial results of interpolated values of the pollutant contamination records that exceeded the established legal limits (represented by homogeneous units up to the neighborhood level) and results of the impact on the exacerbation of pediatric asthma. As a final result, an economic estimate (in Colombian Pesos) of the monthly and individual savings derived from the percentage reduction of the influence of pollutants in relation to visits to the Hospital Emergency Room due to asthma exacerbation in pediatric patients has been granted.

Keywords: Asthma Incidence, BenMap, PM2.5, Statistical Analysis

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Authors: Ricardo Alberto Chiong Zevallos, Eduardo Moraes Rego Reis

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Pancreatic adenocarcinoma (PDAC) patients have a less than 10% 5-year survival rate. PDAC has no defined diagnostic and prognostic biomarkers. Gemcitabine is the first-line drug in PDAC and several other cancers. Long non-coding RNAs (lncRNAs) contribute to the tumorigenesis and are potential biomarkers for PDAC. Although lncRNAs aren’t translated into proteins, they have important functions. LncRNAs can decoy or recruit proteins from the epigenetic machinery, act as microRNA sponges, participate in protein translocation through different cellular compartments, and even promote chemoresistance. The chromatin remodeling enzyme EZH2 is a histone methyltransferase that catalyzes the methylation of histone 3 at lysine 27, silencing local expression. EZH2 is ambivalent, it can also activate gene expression independently of its histone methyltransferase activity. EZH2 is overexpressed in several cancers and interacts with lncRNAs, being recruited to a specific locus. EZH2 can be recruited to activate an oncogene or silence a tumor suppressor. The lncRNAs misregulation in cancer can result in the differential recruitment of EZH2 and in a distinct epigenetic landscape, promoting chemoresistance. The relevance of the EZH2-lncRNAs interaction to chemoresistant PDAC was assessed by Real Time quantitative PCR (RT-qPCR) and RNA Immunoprecipitation (RIP) experiments with naïve and gemcitabine-resistant PDAC cells. The expression of several lncRNAs and EZH2 gene targets was evaluated contrasting naïve and resistant cells. Selection of candidate genes was made by bioinformatic analysis and literature curation. Indeed, the resistant cell line showed higher expression of chemoresistant-associated lncRNAs and protein coding genes. RIP detected lncRNAs interacting with EZH2 with varying intensity levels in the cell lines. During RIP, the nuclear fraction of the cells was incubated with an antibody for EZH2 and with magnetic beads. The RNA precipitated with the beads-antibody-EZH2 complex was isolated and reverse transcribed. The presence of candidate lncRNAs was detected by RT-qPCR, and the enrichment was calculated relative to INPUT (total lysate control sample collected before RIP). The enrichment levels varied across the several lncRNAs and cell lines. The EZH2-lncRNA interaction might be responsible for the regulation of chemoresistance-associated genes in multiple cancers. The relevance of the lncRNA-EZH2 interaction to PDAC was assessed by siRNA knockdown of a lncRNA, followed by the analysis of the EZH2 target expression by RT-qPCR. The chromatin immunoprecipitation (ChIP) of EZH2 and H3K27me3 followed by RT-qPCR with primers for EZH2 targets also assess the specificity of the EZH2 recruitment by the lncRNA. This is the first report of the interaction of EZH2 and lncRNAs HOTTIP and PVT1 in chemoresistant PDAC. HOTTIP and PVT1 were described as promoting chemoresistance in several cancers, but the role of EZH2 is not clarified. For the first time, the lncRNA LINC01133 was detected in a chemoresistant cancer. The interaction of EZH2 with LINC02577, LINC00920, LINC00941, and LINC01559 have never been reported in any context. The novel lncRNAs-EZH2 interactions regulate chemoresistant-associated genes in PDAC and might be relevant to other cancers. Therapies targeting EZH2 alone weren’t successful, and a combinatorial approach also targeting the lncRNAs interacting with it might be key to overcome chemoresistance in several cancers.

Keywords: epigenetics, chemoresistance, long non-coding RNAs, pancreatic cancer, histone modification

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Authors: Eduardo Rodrigues, Gisela Mendes, José M. Torres, José E. Sousa

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In the sequence of the liberalisation of the electricity sector a progressive engagement of consumers has been considered and targeted by sector regulatory policies. With the objective of promoting market competition while protecting consumers interests, by transferring some of the upstream benefits to the end users while reaching a fair distribution of system costs, different market models to value consumers’ demand flexibility at the energy community level are envisioned. Local Energy and Flexibility Markets (LEFM) involve stakeholders interested in providing or procure local flexibility for community, services and markets’ value. Under the scope of DOMINOES, a European research project supported by Horizon 2020, the local market concept developed is expected to: • Enable consumers/prosumers empowerment, by allowing them to value their demand flexibility and Distributed Energy Resources (DER); • Value local liquid flexibility to support innovative distribution grid management, e.g., local balancing and congestion management, voltage control and grid restoration; • Ease the wholesale market uptake of DER, namely small-scale flexible loads aggregation as Virtual Power Plants (VPPs), facilitating Demand Response (DR) service provision; • Optimise the management and local sharing of Renewable Energy Sources (RES) in Medium Voltage (MV) and Low Voltage (LV) grids, trough energy transactions within an energy community; • Enhance the development of energy markets through innovative business models, compatible with ongoing policy developments, that promote the easy access of retailers and other service providers to the local markets, allowing them to take advantage of communities’ flexibility to optimise their portfolio and subsequently their participation in external markets. The general concept proposed foresees a flow of market actions, technical validations, subsequent deliveries of energy and/or flexibility and balance settlements. Since the market operation should be dynamic and capable of addressing different requests, either prioritising balancing and prosumer services or system’s operation, direct procurement of flexibility within the local market must also be considered. This paper aims to highlight the research on the definition of suitable DR models to be used by the Distribution System Operator (DSO), in case of technical needs, and by the retailer, mainly for portfolio optimisation and solve unbalances. The models to be proposed and implemented within relevant smart distribution grid and microgrid validation environments, are focused on day-ahead and intraday operation scenarios, for predictive management and near-real-time control respectively under the DSO’s perspective. At local level, the DSO will be able to procure flexibility in advance to tackle different grid constrains (e.g., demand peaks, forecasted voltage and current problems and maintenance works), or during the operating day-to-day, to answer unpredictable constraints (e.g., outages, frequency deviations and voltage problems). Due to the inherent risks of their active market participation retailers may resort to DR models to manage their portfolio, by optimising their market actions and solve unbalances. The interaction among the market actors involved in the DR activation and in flexibility exchange is explained by a set of sequence diagrams for the DR modes of use from the DSO and the energy provider perspectives. • DR for DSO’s predictive management – before the operating day; • DR for DSO’s real-time control – during the operating day; • DR for retailer’s day-ahead operation; • DR for retailer’s intraday operation.

Keywords: demand response, energy communities, flexible demand, local energy and flexibility markets

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Authors: Eduardo Lanzagorta Garcia, Chaitra Venkatesh, Romina Pezzoli, Laura Gabriela Rodriguez Barroso, Declan Devine, Margaret E. Brennan Fournet

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New antimicrobial interventions are urgently required to combat rising global health and medical infection challenges. Here, an innovative antimicrobial technology, providing price competitive alternatives to antibiotics and readily integratable with currently technological systems is presented. Two cutting edge antimicrobial materials, antimicrobial peptides (AMPs) and uncompromised sustained Ag+ action from triangular silver nanoplates (TSNPs) reservoirs, are merged for versatile effective antimicrobial action where current approaches fail. Antimicrobial peptides (AMPs) exist widely in nature and have recently been demonstrated for broad spectrum of activity against bacteria, viruses, and fungi. TSNP’s are highly discrete, homogenous and readily functionisable Ag+ nanoreseviors that have a proven amenability for operation within in a wide range of bio-based settings. In a design for advanced antimicrobial sustainable plastics, antimicrobial TSNPs are formulated for processing within biodegradable biopolymers. Histone H5 AMP was selected for its reported strong antimicrobial action and functionalized with the TSNP (AMP-TSNP) in a similar fashion to previously reported TSNP biofunctionalisation methods. A synergy between the propensity of biopolymers for degradation and Ag+ release combined with AMP activity provides a novel mechanism for the sustained antimicrobial action of biopolymeric thin films. Nanoplates are transferred from aqueous phase to an organic solvent in order to facilitate integration within hydrophobic polymers. Extrusion is used in combination with calendering rolls to create thin polymerc film where the nanoplates are embedded onto the surface. The resultant antibacterial functional films are suitable to be adapted for food packing and biomedical applications. TSNP synthesis were synthesized by adapting a previously reported seed mediated approach. TSNP synthesis was scaled up for litre scale batch production and subsequently concentrated to 43 ppm using thermally controlled H2O removal. Nanoplates were transferred from aqueous phase to an organic solvent in order to facilitate integration within hydrophobic polymers. This was acomplised by functionalizing the TSNP with thiol terminated polyethylene glycol and using centrifugal force to transfer them to chloroform. Polycaprolactone (PCL) and Polylactic acid (PLA) were individually processed through extrusion, TSNP and AMP-TSNP solutions were sprayed onto the polymer immediately after exiting the dye. Calendering rolls were used to disperse and incorporate TSNP and TSNP-AMP onto the surface of the extruded films. Observation of the characteristic blue colour confirms the integrity of the TSNP within the films. Antimicrobial tests were performed by incubating Gram + and Gram – strains with treated and non-treated films, to evaluate if bacterial growth was reduced due to the presence of the TSNP. The resulting films successfully incorporated TSNP and AMP-TSNP. Reduced bacterial growth was observed for both Gram + and Gram – strains for both TSNP and AMP-TSNP compared with untreated films indicating antimicrobial action. The largest growth reduction was observed for AMP-TSNP treated films demonstrating the additional antimicrobial activity due to the presence of the AMPs. The potential of this technology to impede bacterial activity in food industry and medical surfaces will forge new confidence in the battle against antibiotic resistant bacteria, serving to greatly inhibit infections and facilitate patient recovery.

Keywords: antimicrobial, biodegradable, peptide, polymer, nanoparticle

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Authors: Claire Harrison, Raajit K. Rampal, Vikas Gupta, Srdan Verstovsek, Moshe Talpaz, Jean-Jacques Kiladjian, Ruben Mesa, Andrew Kuykendall, Alessandro Vannucchi, Francesca Palandri, Sebastian Grosicki, Timothy Devos, Eric Jourdan, Marielle J. Wondergem, Haifa Kathrin Al-Ali, Veronika Buxhofer-Ausch, Alberto Alvarez-Larrán, Sanjay Akhani, Rafael Muñoz-Carerras, Yury Sheykin, Gozde Colak, Morgan Harris, John Mascarenhas

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Myelofibrosis (MF) is characterized by bone marrow fibrosis, anemia, splenomegaly and constitutional symptoms. Progressive bone marrow fibrosis results from aberrant megakaryopoeisis and expression of proinflammatory cytokines, both of which are heavily influenced by bromodomain and extraterminal domain (BET)-mediated gene regulation and lead to myeloproliferation and cytopenias. Pelabresib (CPI-0610) is an oral small-molecule investigational inhibitor of BET protein bromodomains currently being developed for the treatment of patients with MF. It is designed to downregulate BET target genes and modify nuclear factor kappa B (NF-κB) signaling. MANIFEST-2 was initiated based on data from Arm 3 of the ongoing Phase 2 MANIFEST study (NCT02158858), which is evaluating the combination of pelabresib and ruxolitinib in Janus kinase inhibitor (JAKi) treatment-naïve patients with MF. Primary endpoint analyses showed splenic and symptom responses in 68% and 56% of 84 enrolled patients, respectively. MANIFEST-2 (NCT04603495) is a global, Phase 3, randomized, double-blind, active-control study of pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve patients with primary MF, post-polycythemia vera MF or post-essential thrombocythemia MF. The aim of this study is to evaluate the efficacy and safety of pelabresib in combination with ruxolitinib. Here we report updates from a recent protocol amendment. The MANIFEST-2 study schema is shown in Figure 1. Key eligibility criteria include a Dynamic International Prognostic Scoring System (DIPSS) score of Intermediate-1 or higher, platelet count ≥100 × 10^9/L, spleen volume ≥450 cc by computerized tomography or magnetic resonance imaging, ≥2 symptoms with an average score ≥3 or a Total Symptom Score (TSS) of ≥10 using the Myelofibrosis Symptom Assessment Form v4.0, peripheral blast count <5% and Eastern Cooperative Oncology Group performance status ≤2. Patient randomization will be stratified by DIPSS risk category (Intermediate-1 vs Intermediate-2 vs High), platelet count (>200 × 10^9/L vs 100–200 × 10^9/L) and spleen volume (≥1800 cm^3 vs <1800 cm^3). Double-blind treatment (pelabresib or matching placebo) will be administered once daily for 14 consecutive days, followed by a 7 day break, which is considered one cycle of treatment. Ruxolitinib will be administered twice daily for all 21 days of the cycle. The primary endpoint is SVR35 response (≥35% reduction in spleen volume from baseline) at Week 24, and the key secondary endpoint is TSS50 response (≥50% reduction in TSS from baseline) at Week 24. Other secondary endpoints include safety, pharmacokinetics, changes in bone marrow fibrosis, duration of SVR35 response, duration of TSS50 response, progression-free survival, overall survival, conversion from transfusion dependence to independence and rate of red blood cell transfusion for the first 24 weeks. Study recruitment is ongoing; 400 patients (200 per arm) from North America, Europe, Asia and Australia will be enrolled. The study opened for enrollment in November 2020. MANIFEST-2 was initiated based on data from the ongoing Phase 2 MANIFEST study with the aim of assessing the efficacy and safety of pelabresib and ruxolitinib in JAKi treatment-naïve patients with MF. MANIFEST-2 is currently open for enrollment.

Keywords: CPI-0610, JAKi treatment-naïve, MANIFEST-2, myelofibrosis, pelabresib

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