Search results for: Sanjay K. Srivastava

Authors: Swati Srivastava, Mattia Lauriola, Yuval Gilad, Adi Kimchi, Yosef Yarden

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The glucocorticoid receptor (GR) has been proposed to play important, but incompletely understood roles in cancer. Glucocorticoids (GCs) are widely used as co-medication of various carcinomas, due to their ability to reduce the toxicity of chemotherapy. Furthermore, GR antagonism has proven to be a strategy to treat triple negative breast cancer and castration-resistant prostate cancer. These observations suggest differential GR involvement in cancer subtypes. The goal of our study has been to elaborate the current understanding of GR signaling in tumor progression and metastasis. Our study involves two cellular models, non-tumorigenic breast epithelial cells (MCF10A) and Ewing sarcoma cells (CHLA9). In our breast cell model, the results indicated that the GR agonist dexamethasone inhibits EGF-induced mammary cell migration, and this effect was blocked when cells were stimulated with a GR antagonist, namely RU486. Microarray analysis for gene expression revealed that the mechanism underlying inhibition involves dexamenthasone-mediated repression of well-known activators of EGFR signaling, alongside with enhancement of several EGFR’s negative feedback loops. Because GR mainly acts primarily through composite response elements (GREs), or via a tethering mechanism, our next aim has been to find the transcription factors (TFs) which can interact with GR in MCF10A cells.The TF-binding motif overrepresented at the promoter of dexamethasone-regulated genes was predicted by using bioinformatics. To validate the prediction, we performed high-throughput Protein Complementation Assays (PCA). For this, we utilized the Gaussia Luciferase PCA strategy, which enabled analysis of protein-protein interactions between GR and predicted TFs of mammary cells. A library comprising both nuclear receptors (estrogen receptor, mineralocorticoid receptor, GR) and TFs was fused to fragments of GLuc, namely GLuc(1)-X, X-GLuc(1), and X-GLuc(2), where GLuc(1) and GLuc(2) correspond to the N-terminal and C-terminal fragments of the luciferase gene.The resulting library was screened, in human embryonic kidney 293T (HEK293T) cells, for all possible interactions between nuclear receptors and TFs. By screening all of the combinations between TFs and nuclear receptors, we identified several positive interactions, which were strengthened in response to dexamethasone and abolished in response to RU486. Furthermore, the interactions between GR and the candidate TFs were validated by co-immunoprecipitation in MCF10A and in CHLA9 cells. Currently, the roles played by the uncovered interactions are being evaluated in various cellular processes, such as cellular proliferation, migration, and invasion. In conclusion, our assay provides an unbiased network analysis between nuclear receptors and other TFs, which can lead to important insights into transcriptional regulation by nuclear receptors in various diseases, in this case of cancer.

Keywords: epidermal growth factor, glucocorticoid receptor, protein complementation assay, transcription factor

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Authors: Soumava Boral, Sanjay K. Chaturvedi, Ian Howard, Kristoffer McKee, V. N. A. Naikan

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Due to strict regulations from government to enhance the possibilities of sustainability practices in industries, and noting the advances in sustainable manufacturing practices, it is necessary that the associated processes are also sustainable. Maintenance of large scale and complex machines is a pivotal task to maintain the uninterrupted flow of manufacturing processes. Appropriate maintenance practices can prolong the lifetime of machines, and prevent associated breakdowns, which subsequently reduces different cost heads. Selection of the best maintenance strategies for such machines are considered as a burdensome task, as they require the consideration of multiple technical criteria, complex mathematical calculations, previous fault data, maintenance records, etc. In the era of the fourth industrial revolution, organizations are rapidly changing their way of business, and they are giving their utmost importance to sensor technologies, artificial intelligence, data analytics, automations, etc. In this work, the effectiveness of several maintenance strategies (e.g., preventive, failure-based, reliability centered, condition based, total productive maintenance, etc.) related to a large scale and complex gearbox, operating in a steel processing plant is evaluated in terms of economic, social, environmental and technical criteria. As it is not possible to obtain/describe some criteria by exact numerical values, these criteria are evaluated linguistically by cross-functional experts. Fuzzy sets are potential soft-computing technique, which has been useful to deal with linguistic data and to provide inferences in many complex situations. To prioritize different maintenance practices based on the identified sustainable criteria, multi-criteria decision making (MCDM) approaches can be considered as potential tools. Multi-Attributive Ideal Real Comparative Analysis (MAIRCA) is a recent addition in the MCDM family and has proven its superiority over some well-known MCDM approaches, like TOPSIS (Technique for Order Preference by Similarity to Ideal Solution) and ELECTRE (ELimination Et Choix Traduisant la REalité). It has a simple but robust mathematical approach, which is easy to comprehend. On the other side, due to some inherent drawbacks of Intuitionistic Fuzzy Sets (IFS) and Pythagorean Fuzzy Sets (PFS), recently, the use of Fermatean Fuzzy Sets (FFSs) has been proposed. In this work, we propose the novel concept of FF-MAIRCA. We obtain the weights of the criteria by experts’ evaluation and use them to prioritize the different maintenance practices according to their suitability by FF-MAIRCA approach. Finally, a sensitivity analysis is carried out to highlight the robustness of the approach.

Keywords: Fermatean fuzzy sets, Fermatean fuzzy MAIRCA, maintenance strategy selection, sustainable manufacturing, MCDM

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Authors: Sumita Srivastava

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Despite several measures taken by the Government of India, entrepreneurship is still not perceived as a viable career option by the young generation. Although the rate of startups has improved a little after the penetration of e portals as business platforms, still the numbers are not very significant. It is also important to note that entrepreneurial initiatives are mostly taken up by graduates of premier institutions of India like Indian Institute of Technology (IITs) and Indian Institute of Management (IIMs). The scenario is not very satisfactory amongst the masses graduating from mainstream universities of the country. Indian youth at large are not attracted towards entrepreneurship as a career choice. The reason probably lies in the social fabric of the country and inappropriate education system which does not support the entrepreneurship at large amongst youth in the country. Education is critical to the development of an economy from the poverty level to the level of self-sustenance and development. The current curriculum in the majority of business schools in India prepares the average graduate to become employed by the available firms or business owners in society. For graduates in other streams, employment opportunities are very limited. The aim of this study was to identify and design entrepreneurship education contents to encourage undergraduates to pursue entrepreneurship as a career choice. This comprehensive study was conducted in multiple stages. Extensive research was conducted at each stage with an appropriate methodology. These stages of the project study were interconnected with each other, and each preceding stage provided inputs for the following stage of the study. In the first stage of the study, an empirical analysis was conducted to understand the current state of entrepreneurial intentions of undergraduates of Agra city. Various stakeholders were contacted at the stage, including students (n = 500), entrepreneurs (n = 20) and academicians and field experts (n = 10). At the second stage of the project study, a systems science technique, Nominal Group Technique (NGT) was used to identify the critical elements of entrepreneurship education in India based upon the findings of stage 1. The application of the Nominal Group Technique involved a workshop format; 15 domain experts participated in the workshop. Throughout the process, a democratic process was followed to avoid individual dominance and premature focusing on a single idea. The study obtained 63 responses from experts for effective entrepreneurship education in India. The responses were reduced to seven elements after a few thematic iterations. These elements were then segregated into content (knowledge, skills and attitude) and learning interaction on the basis of experts’ responses. After identifying critical elements of entrepreneurship education in the previous stage, the course was designed and validated at stage 3 of the project. Scientific methods were used at this stage to validate the curriculum contents and training interventions experimentally. The educational and training interventions designed through this study would not only help in developing entrepreneurial intentions but also creating skills relevant to the local entrepreneurial opportunities in the vicinity.

Keywords: curriculum design, entrepreneurial intention, entrepreneuship education, nominal group technique

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Authors: Jeet Chakraborty, Sanjay Dutta

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Antibiotic resistance by bacteria has proved to be a severe threat to mankind in recent times, and this fortifies an urgency to design and develop potent antibacterial small molecules/compounds with nonconventional mechanisms than the conventional ones. DNA carries the genetic signature of any organism, and bacteria maintain their genomic DNA inside the cell in a well-regulated compact form with the help of various nucleoid associated proteins like HU, HNS, etc. These proteins control various fundamental processes like gene expression, replication, etc., inside the cell. Alteration of the native DNA structure of bacteria can lead to severe consequences in cellular processes inside the bacterial cell that ultimately result in the death of the organism. The change in the global DNA structure by small molecules initiates a plethora of cellular responses that have not been very well investigated. Echinomycin and Triostin-A are biologically active Quinoxaline small molecules that typically consist of a quinoxaline chromophore attached with an octadepsipeptide ring. They bind to double-stranded DNA in a sequence-specific way and have high activity against a wide variety of bacteria, mainly against Gram-positive ones. To date, few synthetic quinoxaline scaffolds were synthesized, displaying antibacterial potential against a broad scale of pathogenic bacteria. QNOs (Quinoxaline N-oxides) are known to target DNA and instigate reactive oxygen species (ROS) production in bacteria, thereby exhibiting antibacterial properties. The divergent role of Quinoxaline small molecules in medicinal research qualifies them for the evaluation of their antimicrobial properties as a potential candidate. The previous study from our lab has given new insights on a 6-nitroquinoxaline derivative 1d as an intercalator of DNA, which induces conformational changes in DNA upon binding.7 The binding event observed was dependent on the presence of a crucial benzyl substituent on the quinoxaline moiety. This was associated with a large induced CD (ICD) appearing in a sigmoidal pattern upon the interaction of 1d with dsDNA. The induction of DNA superstructures by 1d at high Drug:DNA ratios was observed that ultimately led to DNA condensation. Eviction of invitro-assembled nucleosome upon treatment with a high dose of 1d was also observed. In this work, monoquinoxaline derivatives of 1d were synthesized by various modifications of the 1d scaffold. The set of synthesized 6-nitroquinoxaline derivatives along with 1d were all subjected to antibacterial evaluation across five different bacteria species. Among the compound set, 3a displayed potent antibacterial activity against Staphylococcus aureus bacteria. 3a was further subjected to various biophysical studies to check whether the DNA structural alteration potential was still intact. The biological response of S. aureus cells upon treatment with 3a was studied using various cell biology processes, which led to the conclusion that 3d can initiate DNA damage in the S. aureus cells. Finally, the potential of 3a in disrupting preformed S.aureus and S.epidermidis biofilms was also studied.

Keywords: DNA structural change, antibacterial, intercalator, DNA superstructures, biofilms

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Authors: Sanjay Ranade

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Traditional film theory assumes the cinema audience in a darkened room where cinema is projected on to a white screen, and the audience suspends their sense of reality. Shifts in audiences due to changes in cultural tastes or trends have been studied for decades. In the past two decades, however, the audience, especially the youth, has shifted to digital media for the consumption of cinema. As a result, not only are audiences watching cinema on different devices, they are also consuming cinema in places and ways never imagined before. Public transport often crowded to the brim with a lot of ambient content, and a variety of workplaces have become sites for cinema viewing. Cinema is watched piecemeal and at different times of the day. Audiences use devices such as mobile phones and tablets to watch cinema. The cinema viewing experience is getting redesigned by the user. The emerging design allows the spectator to not only consume images and narratives but also produce, reproduce, and manipulate existing images and narratives, thereby participating in the process and influencing it. Spectatorship studies stress on the importance of subjectivity when dealing with the structure of the film text and the cultural and psychological implications in the engagement between the spectator and the film text. Indian cinema has been booming and contributing to global movie production significantly. In 2005 film production was 1000 films a year and doubled to 2000 by 2016. Digital technology helped push this growth in 2012. Film studies in India have had a decided Euro-American bias. The studies have chiefly analysed the content for ideological leanings or myth or as reflections of society, societal changes, or articulation of identity or presented retrospectives of directors, actors, music directors, etc. The one factor relegated to the background has been the spectator. If they have been addressed, they are treated as a collective of class or gender. India has a performative tradition going back several centuries. How Indians receive cinema is an important aspect to study with respect to film studies. This exploratory and descriptive study looked at 162 young media students studying cinema at the undergraduate and postgraduate levels. The students, speaking as many as 20 languages amongst them, were drawn from across the country’s media schools. The study looked at nine film societies registered with the Federation of Film Societies of India. A structured questionnaire was made and distributed online through media teachers for the students. The film societies were approached through the regional office of the FFSI in Mumbai. Lastly, group discussions were held in Mumbai with students and teachers of media. A group consisted of between five and twelve student participants, along with one or two teachers. All the respondents looked at themselves as spectators and shared their experiences of spectators of cinema, providing a very rich insight into Indian conditions of viewing cinema and challenges for cinema ahead.

Keywords: audience, digital, film studies, reception, reception spectatorship

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Authors: Rasmila Kawan, Sanjay Juvekar, Sandeep Salvi, Gufran Beig, Rainer Sauerborn

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Background: Indoor air pollution especially from the use of biomass fuels, remains a potentially large global health threat. The inefficient use of such fuels in poorly ventilated conditions results in high levels of indoor air pollution, most seriously affecting women and young children. Objectives: The main aim of this study was to measure and compare the lung function of the women exposed in the biomass fuels and LPG fuels and relate it to the indoor emission measured using a structured questionnaire, spirometer and filter based low volume samplers respectively. Methodology: This cross-sectional comparative study was conducted among the women (aged > 18 years) living in rural villages of Pune district who were not diagnosed of chronic pulmonary diseases or any other respiratory diseases and using biomass fuels or LPG for cooking for a minimum period of 5 years or more. Data collection was done from April to June 2017 in dry season. Spirometer was performed using the portable, battery-operated ultrasound Easy One spirometer (Spiro bank II, NDD Medical Technologies, Zurich, Switzerland) to determine the lung function over Forced expiratory volume. The primary outcome variable was forced expiratory volume in 1 second (FEV1). Secondary outcome was chronic obstruction pulmonary disease (post bronchodilator FEV1/ Forced Vital Capacity (FVC) < 70%) as defined by the Global Initiative for Obstructive Lung Disease. Potential confounders such as age, height, weight, smoking history, occupation, educational status were considered. Results: Preliminary results showed that the lung function of the women using Biomass fuels (FEV1/FVC = 85% ± 5.13) had comparatively reduced lung function than the LPG users (FEV1/FVC = 86.40% ± 5.32). The mean PM 2.5 mass concentration in the biomass user’s kitchen was 274.34 ± 314.90 and 85.04 ± 97.82 in the LPG user’s kitchen. Black carbon amount was found higher in the biomass users (black carbon = 46.71 ± 46.59 µg/m³) than LPG users (black carbon=11.08 ± 22.97 µg/m³). Most of the houses used separate kitchen. Almost all the houses that used the clean fuel like LPG had minimum amount of the particulate matter 2.5 which might be due to the background pollution and cross ventilation from the houses using biomass fuels. Conclusions: Therefore, there is an urgent need to adopt various strategies to improve indoor air quality. There is a lacking of current state of climate active pollutants emission from different stove designs and identify major deficiencies that need to be tackled. Moreover, the advancement in research tools, measuring technique in particular, is critical for researchers in developing countries to improve their capability to study the emissions for addressing the growing climate change and public health concerns.

Keywords: black carbon, biomass fuels, indoor air pollution, lung function, particulate matter

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Authors: Manushi Srivastava

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Introduction: Doctor’s role, and relation with respect to patient care is at the core of medical ethics. The rapid pace of medical advances along with increasing consumer awareness about their rights and hike in cost of effective health care demand a robust, transparent and patient-friendly medical care system. However, doctors’ role performance is still in the frame of activity-passivity model of Doctor-Patient Relationship (DPR) where doctors act as parent and use to instruct their patients, without their consensus that is not going to help in the 21st century. Thus the current situation is a new challenge for traditional doctor-patient relationship after the introduction of Consumer Protection Act (CPA) in medical profession and the same is evidenced by increasing cases of medical litigation. To strengthen this system of medical services, the doctor plays a vital role, and the same should be reviewed in the present context. Objective: To understand the opinion of consultants regarding medical negligence and effect of Consumer Protection Act in terms of current practices of patient care. Method: This is a cross-sectional study in which both quantitative and qualitative methods are applied. Total 69 consultants were selected from multi-specialty hospitals of densely populated Varanasi city catering a population of about 1.8 million. Two-stage sampling was used for selection of respondents. At the first stage, selection of major wards (Medicine, Surgery, Ophthalmology, Gynaecology, Orthopaedics, and Paediatrics) was carried out, which are more susceptible to medical negligence. At the second stage, selection of consultants from the respective wards was carried out. In-depth Interviews were conducted with the help of semi-structured schedule. Two case studies of medical negligence were also carried out as part of the qualitative study. Analysis: Data were analyzed with the help of SPSS software (21.0 trial version). Semi-structured research tool was used to know consultant’s opinion about the pattern of medical negligence cases, litigations and claims made by patient community and inclusion of government medical services in CPA. Statistical analysis was done to describe data, and non-parametric test was used to observe the association between the variables. Analysis of Verbatim was used in case-study. Findings and Conclusion: Majority (92.8%) of consultants felt changes in the behaviour of community (patient) after implementation of CPA, as it had increased awareness about their rights. Less than half of the consultants opined that Medical Negligence is an Unintentional act of doctors and generally occurs due to communication gap and behavioural problem between doctor and patients. Experienced consultants ( > 10 years) pointed out that unethical practice by doctors and mal-intention of patient to harass doctors were additional reasons of Medical Negligence. In-depth interview revealed that now patients’ community expects more transparency and hence they demand cafeteria approach in diagnosis and management of cases. Thus as study results, we propose ‘Agreement Model’ of DPR to re-ensure ethical practice in medical profession.

Keywords: doctors, communication, consumer protection act (CPA), medical error

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Authors: Kaushalendra Kumar, Abhishek Kumar, Chandra Moni, Sanjay Kumar, P. K. Singh, Ajeet Kumar

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Present study investigated the dietary inclusion of Moringa oleifera leaf meal (MOLM) on production efficiency, hemato-biochemical profile and economy of Vanaraja birds under tropical condition. Experiment was conducted for a period of 56 days on 300 Vanaraja birds randomly divided in to five different experimental groups including control of 60 birds each group replicated with 20 chicks in each replicate. T1, T2, T3, T4, and T5 were offered with 0, 5, 10, 15, and 20% Moringa oleifera leaf meal along with basal ration. All the standard managemental practices were followed during experimental period including vaccination schedule. Locally available Moringa oleifera leaves were harvested at mature stage and allowed to dry under shady and aerated conditions. Thereafter, dried leaves were milled to make a leaf meal and stored in the airtight nylon bags to avoid any possible contamination from foreign material and use for experiment. Production parameters were calculated based on the amount of feed consumed and weight gain every weeks. The body weight gain of T2 group was significantly (P < 0.05) higher side whereas T3 group was comparable with control. The feed conversion ratio for T2 group was found to be significantly (P < 0.05) lower than all other treatment groups, while none of the group was comparable with each other. At the end of the experiment blood samples were collected from birds for haematology study while serum biochemistry performed using spectrophotometer following statndard protocols. The haematological attributes were significantly (P > 0.05) not differed among the groups. However, serum biochemistry showed significant reduction (P < 0.05) of blood urea nitrogen, uric acid and creatinine level with higher level of MOLM diet, indicates better utilization of protein supplemented through MOLM. The total cholesterol and triglyceride level was declined significantly (P < 0.05) as compare to control group with increased level of MOLM in basal diet, decreasing trend of serum cholesterol noted. However, value of HDL for T3 group was highest and for T1 group was lowest but no significant difference (P < 0.05) found among the groups. It might be due to presence of β-sitosterol a bioactive compound present in MOLM which causes lowering of plasma concentration of LDL. During experiment total, LDL and VLDL level was found to be decreased significantly (P < 0.05) as compare to control group. It was observed that the production efficiency of birds significantly improved with 5% followed by 10% Moringa oleifera leaf meal among the treatment groups. However, the maximum profit per kg live weight was noted in 10 % level and least profit observed in 20% MOLM fed group. It was concluded that the dietary inclusion of MOLM improved overall performances without affecting metabolic status and effective in reducing cholesterol level reflects healthy chicken production for human consumption.

Keywords: hemato biochemistry, Moringa oleifera leaf meal, performance, Vanaraja birds

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Authors: Hari Krishan Sharma, Sanjay Kumar Sharma, Sushil Kumar Swar

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Inadequate transverse reinforcement is considered as the main reason for the beam column joint shear failure observed during recent earthquakes. DSP matrix consists of cement and high content of micro-silica with low water to cement ratio while the aggregates are graded quartz sand. The use of reinforcing fibres leads not only to the increase of tensile/bending strength and specific fracture energy, but also to reduction of brittleness and, consequently, to production of non-explosive ruptures. Besides, fibre-reinforced materials are more homogeneous and less sensitive to small defects and flaws. Recent works on the freeze-thaw durability (also in the presence of de-icing salts) of fibre-reinforced DSP confirm the excellent behaviour in the expected long term service life.DSP materials, including fibre-reinforced DSP and CRC (Compact Reinforced Composites) are obtained by using high quantities of super plasticizers and high volumes of micro-silica. Steel fibres with high tensile yield strength of smaller diameter and short length in different fibre volume percentage and aspect ratio tilized to improve the performance by reducing the brittleness of matrix material. In the case of High Performance Densified Small Particle Concrete (HPDSPC), concrete is dense at the micro-structure level, tensile strain would be much higher than that of the conventional SFRC, SIFCON & SIMCON. Beam-column sub-assemblages used as moment resisting constructed using HPDSPC in the joint region with varying quantities of steel fibres, fibre aspect ratio and fibre orientation in the critical section. These HPDSPC in the joint region sub-assemblages tested under cyclic/earthquake loading. Besides loading measurements, frame displacements, diagonal joint strain and rebar strain adjacent to the joint will also be measured to investigate stress-strain behaviour, load deformation characteristics, joint shear strength, failure mechanism, ductility associated parameters, stiffness and energy dissipated parameters of the beam column sub-assemblages also evaluated. Finally a design procedure for the optimum design of HPDSPC corresponding to moment, shear forces and axial forces for the reinforced concrete beam-column joint sub-assemblage proposed. The fact that the implementation of material brittleness measure in the design of RC structures can improve structural reliability by providing uniform safety margins over a wide range of structural sizes and material compositions well recognized in the structural design and research. This lead to the development of high performance concrete for the optimized combination of various structural ratios in concrete for the optimized combination of various structural properties. The structural applications of HPDSPC, because of extremely high strength, will reduce dead load significantly as compared to normal weight concrete thereby offering substantial cost saving and by providing improved seismic response, longer spans, and thinner sections, less reinforcing steel and lower foundation cost. These cost effective parameters will make this material more versatile for use in various structural applications like beam-column joints in industries, airports, parking areas, docks, harbours, and also containers for hazardous material, safety boxes and mould & tools for polymer composites and metals.

Keywords: high performance densified small particle concrete (HPDSPC), steel fibre reinforced concrete (SFRC), slurry infiltrated concrete (SIFCON), Slurry infiltrated mat concrete (SIMCON)

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Authors: Anjula Negi, Sanjay Gupta

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Paradigms studied inform inadequacies of financial resources, be it to finance metro rails for construction or to meet operational revenues or to derive profits in the long term. Funding sustainability is far and wide for much-needed public transport modes, like urban rail or metro rails, to be successfully operated. India embarks upon a sustainable transport journey and has proposed metro rail systems countrywide. As an emerging economic leader, its fiscal constraints are paramount, and the land value capture (LVC) mechanism provides necessary support and innovation toward development. India’s metro rail policy promotes multiple methods of financing, including private-sector investments and public-private-partnership. The critical question that remains to be addressed is what factors can make such mechanisms work. Globally, urban rail is a revolution noted by many researchers as future mobility. Researchers in this study deep dive by way of literature review and empirical assessments into factors that can lead to the adoption of LVC mechanisms. It is understood that the adoption of LVC methods is in the nascent stages in India. Research posits numerous challenges being faced by metro rail agencies in raising funding and for incremental value capture. A few issues pertaining to land-based financing, inter alia: are long-term financing, inter-institutional coordination, economic/ market suitability, dedicated metro funds, land ownership issues, piecemeal approach to real estate development, property development legal frameworks, etc. The question under probe is what are the parameters that can lead to success in the adoption of land value capture (LVC) as a financing mechanism. This research provides insights into key parameters crucial to the adoption of LVC in the context of Indian metro rails. Researchers have studied current forms of LVC mechanisms at various metro rails of the country. This study is significant as little research is available on the adoption of LVC, which is applicable to the Indian context. Transit agencies, State Government, Urban Local Bodies, Policy makers and think tanks, Academia, Developers, Funders, Researchers and Multi-lateral agencies may benefit from this research to take ahead LVC mechanisms in practice. The study deems it imperative to explore and understand key parameters that impact the adoption of LVC. Extensive literature review and ratification by experts working in the metro rails arena were undertaken to arrive at parameters for the study. Stakeholder consultations in the exploratory factor analysis (EFA) process were undertaken for principal component extraction. 43 seasoned and specialized experts participated in a semi-structured questionnaire to scale the maximum likelihood on each parameter, represented by various types of stakeholders. Empirical data was collected on chosen eighteen parameters, and significant correlation was extracted for output descriptives and inferential statistics. Study findings reveal these principal components as institutional governance framework, spatial planning features, legal frameworks, funding sustainability features and fiscal policy measures. In particular, funding sustainability features highlight sub-variables of beneficiaries to pay and use of multiple revenue options towards success in LVC adoption. Researchers recommend incorporation of these variables during early stage in design and project structuring for success in adoption of LVC. In turn leading to improvements in revenue sustainability of a public transport asset and help in undertaking informed transport policy decisions.

Keywords: Exploratory factor analysis, land value capture mechanism, financing metro rails, revenue sustainability, transport policy

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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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