Transcriptomic data integration for precision medicine in leukemia

This thesis is comprised of three studies demonstrating the application of different statistical and bioinformatic approaches to address distinct challenges of implementing precision medicine strategies for hematological malignancies. The approaches focus on the analysis of next-generation sequencing data, including both genomic and transcriptomics, to deconvolute disease biology and underlying mechanisms of drug sensitivities and resistance. The outcomes of the studies have clinical implications for advancing current diagnosis and treatment paradigms in patients with hematological diseases. Study I, RNA sequencing has not been widely adopted in a clinical diagnostic setting due to continuous development and lack of standardization. Here, the aim was to evaluate the efficiency of two different RNA-seq library preparation protocols applied to cells collected from acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. The poly-A-tailed mRNA selection (PA) and ribo- depletion (RD) based RNA-seq library preparation protocols were compared and evaluated for detection of gene fusions, variant calling and gene expression profiling. Overall, both protocols produced broadly consistent results and similar outcomes. However, the PA protocol was more efficient in quantifying expression of leukemia marker genes and drug targets. It also provided higher sensitivity and specificity for expression-based classification of leukemia. In contrast, the RD protocol was more suitable for gene fusion detection and captured a greater number of transcripts. Importantly, high technical variations were observed in samples from two leukemia patient cases suggesting further development of strategies for transcriptomic quantification and data analysis. Study II, the BCL-2 inhibitor venetoclax is an approved and effective agent in combination with hypomethylating agents or low dose cytarabine for AML patients, unfit for intensive induction chemotherapy. However, a limited number of patients responding to venetoclax and development of resistance to the treatment presents a challenge for using the drug to benefit the majority of the AML patients. The aim was to investigate genomic and transcriptomic biomarkers for venetoclax sensitivity and enable identification of the patients who are most responsive to venetoclax treatment. We found that venetoclax sensitive samples are enriched with WT1 and IDH1/IDH2 mutations. Intriguingly, HOX family genes, including HOXB9, HOXA5, HOXB3, HOXB4, were found to be significantly overexpressed in venetoclax sensitive patients. Thus, these HOX-cluster genes expression biomarkers can be explored in a clinical trial setting to stratify AML patients responding to venetoclax based therapies. Study III, venetoclax treatment does not benefit all AML patients that demands identifying biomarkers to exclude the patients from venetoclax based therapies. The aim was to investigate transcriptomic biomarkers for ex vivo venetoclax resistance in AML patients. The correlation of ex vivo venetoclax response with gene expression profiles using a machine learning approach revealed significant overexpression of S100 family genes, S100A8 and S100A9. Moreover, high expression ofS100A9was found to be associated with birabresib (BET inhibitor) sensitivity. The overexpression of S100A8 and S100A9 could potentially be used to detect and monitor venetoclax resistance. The combination of BCL-2 and BET inhibitors may sensitize AML cells to venetoclax upon BET inhibition and block leukemic cell survival.In this thesis, the aim was to utilize gene expression information for advanced precision medicine outcomes in patients with hematological malignancies. In the study, I, the contemporary mainstream library preparation protocols, Ribo-depletion and PolyA enrichment used for RNA sequencing, were compared in order to select the protocol that suffices the goal of the experiment, especially in patients with acute leukemias. In study II, we applied bioinformatics approaches to identify IDH1/2 mutation and HOX family gene expression correlated with ex vivo sensitivity to BCL-2 inhibitor venetoclax in acute myeloid leukemia (AML) patients. In study III, statistical and machine learning methods were implemented to identify S100A8/A9 gene expression biomarkers for ex vivo resistance to venetoclax in AML patients. In summary, this thesis addresses the challenges of utilizing gene expression information to stratify patients based on biomarkers to promote precision medicine practice in hematological malignancies

MEDICINAL PROPERTIES OF BALA (SIDA CORDIFOLIA LINN. AND ITS SPECIES)

The Indian system of medicine, Ayurveda, medical science practiced for a long time for disease free life. It relies mainly upon the medicinal plants (herbs) for the management of various ailments/diseases. Bala (Sida cordifolia Linn.) that is also known as Indian Ephedra is a plant drug, which is used in the various medicines in Ayurveda, Unani and Siddha system of medicine since ages. It has good medicinal value and useful to treat diseases like fever, weight loss, asthma, chronic bowel complaints and nervous system disease and acts as analgesic, anti-inflammatory, hypoglycemic activities etc. Bala is described as Rasayan, Vishaghana, Balya and Pramehaghna in the Vedic literature. Caraka described Bala under Balya, Brumhani dashaimani, while Susruta described both Bala and Atibala in Madhur skandha. It is extensively used for Ayurvedic therapeutics internally as well as externally. The root of the herb is used as a good tonic and immunomodulator. Atibala is in Atharva Parisista along with Bala and other drugs. Caraka described it among the Balya group of drugs whereas Carakapani considered it as Pitbala. Atibala is quoted in the Nighantus in the context of Bala catustaya. Nagbala or Gangaruki are not found in vedic literature. Nagbala term is used by Brhat trayi repeatedly whereas Gangeruki which is synonym of Nagbala is mentioned thrice only. The present review explained on the sida species and the traditional uses, Ayurvedic preparation and pharmacological properties

MEDICINAL PROPERTIES OF APAMARG (ACHYRANTHES ASPERA LINN.)

The Indian system of medicine, Ayurveda, a medical science practiced for a long time for disease free life. It relies mainly upon the medicinal plants for the management of various diseases. Among these herbs Apamarg (Achyranthes Aspera Linn.) is very important and easily available herb mentioned in Vedic literature and in Atharvaveda, considered as lord of all plants on earth. This medicinal plant found as a weed throughout India up to 900 m. Though almost all of its parts are used in traditional system of medicines, seeds, roots, and shoots are the most important parts, which are used medicinally. The present article gives important information on therapeutic uses, traditional medicinal uses mentioned in various Samhitas and Nighantus, phytochemical and pharmacological properties of modern era

A Comparative Study of Manoj Das’s Akasara Isara (Odia) and The Escapist (English)

There are very few bilingual writers of repute in the country and Manoj Das distinctly stands as a prolific writer who has carved a niche for himself in this arena. In fact, he is one of the greatest writers of the country, who has given a new direction to the bilingual writing and proved his brilliance through his great short stories and novels both in Odia and English languages with his creative genius. He is one of the widely acclaimed bilingual story tellers of the country whose writings have been accepted by the readers for their novelty of thoughts and flawless narration. Many prestigious literary awards like the Sahitya Akademi Award, the Padma Shri and the Saraswati Samman and many more have been bestowed upon him. He is in fact one of the towering literary personalities in the Indian English fictions arena who has been instrumental in establishing a native identity. His in-depth analysis of human emotions and their universal appeal is something that is amazingly brilliant in his writings. He has been widely acclaimed and appreciated for his literary genius and creative brilliance. The present research article attempts a comparative study of these two novels which are unique with their thematic treatment as well as the subtle realities combined with powerful philosophical messages. His novel Akasara Isara (1997) which originally appeared in Odia and later translated by the author himself in English as The Escapist (2001) describes the human tragedy against the backdrop of an all-pervading destiny. The article discusses such issues of translation and bilingual writing. It also focuses on the cultural aspects

Towards a Knowledge Graph based Speech Interface

Applications which use human speech as an input require a speech interface with high recognition accuracy. The words or phrases in the recognised text are annotated with a machine-understandable meaning and linked to knowledge graphs for further processing by the target application. These semantic annotations of recognised words can be represented as a subject-predicate-object triples which collectively form a graph often referred to as a knowledge graph. This type of knowledge representation facilitates to use speech interfaces with any spoken input application, since the information is represented in logical, semantic form, retrieving and storing can be followed using any web standard query languages. In this work, we develop a methodology for linking speech input to knowledge graphs and study the impact of recognition errors in the overall process. We show that for a corpus with lower WER, the annotation and linking of entities to the DBpedia knowledge graph is considerable. DBpedia Spotlight, a tool to interlink text documents with the linked open data is used to link the speech recognition output to the DBpedia knowledge graph. Such a knowledge-based speech recognition interface is useful for applications such as question answering or spoken dialog systems.Comment: Under Review in International Workshop on Grounding Language Understanding, Satellite of Interspeech 201

Cross-layer Based MANET Performance Optimization for Different Traffic and Mobility Scenario

The self configuring dexterous autonomy of MANET imposes some network challenges constrained to traditional dynamic routing behaviour. So as working with different mobility and traffic patterns with normal management schemes may lead some minor pitfalls to some important network performance parameters and hence can degrade the whole network performance. Here,  Our aim is to make some DSR and MAC based cross layer optimizations and testify it on different mobility and traffic scenarios so as to justify the robustness of our proposed improvement. Keywords— Cross- Layer, DSR, MAC, MANET, Optimizatio

High Isolation Wideband MIMO Antenna without Decoupling Technique for IoT Applications

This paper presents a method a high isolation wideband MIMO antenna without using any decoupling technique. This is achieved by transforming a strip line to a 1 ×2 MIMO antenna using Hilbert transform and Defected Ground structure is used in the antenna to resonate the antenna in for IOT and  5G sub-6 GHz bands. The proposed antenna has a size of 50 × 49.8 × 1.6 mm 3 and operates in the frequency band of 4.6 GHz to 5.94 GHz. The antenna simulated in ANSYS HFSS showed that its parameters Envelope correlation coefficient (ECC), Total Active Reflection Coefficient (TARC), Diversity gain (DG) and Channel Capacity Loss (CCL) are less than 0.04, -25 dB, 9.98 to 10 dB and less than 0.4 bits/s/Hz respectively. The radiation pattern of the antenna in both E-plane and H-plane has been simulated which the uniform distribution of power in the space

Modelling and simulation of 3D orthogonal and interlock fabrics for structural composite applications

Modelling and simulation of 3D orthogonal and interlock fabrics have been studied for tensile applications. Thisinvolves building a geometrical model by calculating the proper dimensions of the tows, conversion of the geometricalmodel into finite element mesh, and subsequently, prediction of tensile properties in the direction of load bearing tows bysimulation using meso-finite element modelling. For the simulation, elliptical tow cross-section with aspect ratio 11 hasbeen preferred as the best geometrical modelling parameter. Model results obtained from finite element analysis are thencompared with experimental values to authenticate the modelling methodologies. The simulated results of maximum stressat break are found to be higher than the experimental results for both the corresponding orthogonal and interlock structures

Body Sensor Network: A Modern Survey & Performance Study in Medical Perspect

As because of modern emerging technologies, low power integrated circuits and wireless communication has enabled a new generation of sensors network. The incorporation of these sensors networks in Health care is very popular and plays a vital role in breath breaking situations. The deployment of monitoring hardware incorporated with various wireless standards plays a key role in regard to interoperability, invasion privacy, sensors validation data consistency and interference related issues. The goal of our paper is to make a comparative study in realm of modern wireless trends such as Bluetooth, Wi-fi, Zigbee and Wibree and related facets. Index Terms– Wireless Body area network, Zigbee, Wi-fi, Bluetooot

Quality of Service Optimization in Realm of Green Monitoring using Broad Area Sensor Network (BASN)

A Wireless Sensor Network(WSN) contains short range energy limited terminals/nodes in which multiple nodes participates one by one to transfer data from source node to Base station. Each node appends some amount of delay which degrades the network performance as the jittered behaviour of network may not be allowed in some applications. Again the faulty nature of tandem nodes may create some severe routing scenarios.  Concept of Broad Area Sensor Network (BASN) incorporates a real time communication between sensor node and Base station, which helps to optimize the Quality of Service (QoS). Our goal is to do extensive simulation on performance analysis of such sensor networks and its optimization. Keywords -  WSN ,energy limited terminals, jitter, Quality of service(QoS