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Home > Plasma Proteomics Analysis of Hydroxyurea Treated Patients Suffering from Thalassemia

Plasma Proteomics Analysis of Hydroxyurea Treated Patients Suffering from Thalassemia

Thesis Info

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Author

Zohaib, Muhammad

Program

PhD

Institute

University of Karachi

City

Karachi

Province

Sindh

Country

Pakistan

Thesis Completing Year

2019

Thesis Completion Status

Completed

Subject

Chemistry

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/11521/1/Muhammad%20Zohaib%202019%20Biochemistry.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676726956503

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β thalassemia is the most prevalent autosomal recessive disorder characterized by absence or reduced production of hemoglobin (Hb) levels, primarily caused by mutations on β globin locus. β thalassemia is heterogeneous at the molecular level, presenting variable phenotypes accompanied with severe medical complications. Current standard of care for clinical management of β thalassemia includes regular, long-life safe blood transfusion along with appropriate iron chelation therapy. At present, the only permanent cure is bone marrow transplantation. An emerging and exciting therapeutic approach to handle β thalassaemia is production of fetal hemoglobin (HbF) which is major Hb of fetal life. In recent years, Hydroxyurea (HU) has proven to be a promising HbF augmenting agent but response to HU therapy varies from transfusion elimination to insignificant clinical response. Various approaches are being made to understand the mechanism HbF augmentation with differential responses. Advancement in proteomics offers an efficient tool to study differential proteome in response to treatment leading towards precision and personalized medicine. This study is designed to improve mechanistic understanding of proteomic changes that HU therapy exerted on β thalassemia patients, in consort with deciphering differential protein expression in HU responder and non-responder. Firstly, samples were subjected to twodimensional gel electrophoresis to assess differentially expressed proteins. Later, differential proteins were identified by label free quantitative proteomics approach. Two hundred and eighty seven proteins were identified with two or more unique peptides in samples studied. Among these, twenty eight proteins were found to be significantly different in pre versus post HU treated β thalassemia patients at probability of < 0.05. Eighteen proteins were down-regulated while ten were found to be up-regulated after HU treatment. Clinically important proteins include Hemopexin (HPX), Haptoglobin (HP), Haptoglobin-related protein (HPR), Hemoglobin subunit beta (HBB), Hemoglobin subunit delta (HBD), Hemoglobin subunit alpha (HBA1), Protein S100-A8 (S100A8), Apolipoprotein L1 (APOL1), Apolipoprotein C-I (APOC1), Transferrin receptor protein (TFRC), Complement C4-A (C4A), Apolipoprotein A (LPA), Ceruloplasmin (CP) and Ficolin-3 (FCN3). HU therapy in β thalassemia patients started reverting protein profile towards healthy pattern, in addition with decrease in transfusion requirements. A follow up study on plasma of HU treated β thalassemia patients was performed to compare proteomic profile of HU responder and non-responder. Twenty six proteins were found to be differentially expressed in HU responder versus non-responder at p < 0.05. Among these, fifteen proteins showed a significantly increased level while eleven proteins revealed a decreased in expression. Clinically relevant altered proteins in HU responder are Peroxiredoxin-2 (PRDX2), Carbonic anhydrase 1(CA1), Hemoglobin subunit gamma-1 (HBG1),Hemoglobin subunit beta (HBB), Hemoglobin subunit delta (HBD), Hemoglobin subunit alpha (HBA1), Properdin (CFP), Cholinesterase (BCHE), Phospholipid transfer protein (PLTP) and Plasma protease C1 inhibitor (SERPING1). We suggest that further research would be required for validation of identified proteins in large cohort to endorse as potential predictive biomarker for HU therapy. Considering the association of oxidative stress with β thalassemia, we also studied markers of oxidative stress in response to HU therapy in β thalassemia covering Paraoxonase1 (PON1), Reactive oxygen species (ROS), and Malondialdehyde (MDA). Although PON1 serve as an antioxidant to reduce the adverse effects of the oxidative stress in β thalassemia, our results indicate that mode of action of HU may not directly be through oxidative imbalance
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تعلیمِ نسواں

تعلیم نسواں
علم جہاں پہنچتا ہے اندھیرے سے نکال کر روشنی میں لے جاتا ہے ،ظلمت سے ضیاء کی طرف روانگی ہو جاتی ہے، جہالت سے شعور وآگہی کا سفر شروع ہو جاتا ہے۔ علم ایک ایسی دولت ہے جو انسان کواوجِ ثرّیا تک پہنچا دیتی ہے۔ علم ایک ایسازینہ ہے جس سے معرفتِ الٰہی کے محل کی طرف رسائی ممکن ہے۔ علم کے زیور سے مرصعّ شخص معاشرے کے ماتھے کا جھومر ہوتے ہیں۔ علم کی حقیقتوں سے آشنائی ایک عظمت ہے اس طرح عورت علم کے زیور سے مزیّن ہوگی تو معاشرہ سنور جائے گا۔
مردوں کی بھی تعلیم ضروری تو ہے مگر
پڑھ جائے جو خاتون تو نسلیں سنوار دے
تعلیم نسواں سے مراد عورتوں کی تعلیم ہے۔ مردوں کی طرح عورتوں کے لیے بھی حصول علم بہت ضروری ہے۔ عورت اور مرد زندگی کی گاڑی کے دو پہیے ہیں۔ ان دونوں پہیوں کا صحیح ہونا بہت ضروری ہے۔ ورنہ زندگی کی گاڑی ٹھیک طرح سے چل نہ سکے گی۔ کوئی قوم اس وقت تک ترقی نہیں کرسکتی جب تک اس قوم کی عورتیں زیورِ تعلیم سے آراستہ نہ ہوں۔
نبی کریم صلی اللہ علیہ و آلہٖ وسلمکا ارشاد ہے کہ’’ علم حاصل کرنا ہر مسلمان مرد اور عورت پر فرض ہے۔‘‘ اس حدیث مبارکہ سے مرد اور عورت دونوں کی خاطر علم کی اہمیت واضح ہوتی ہے۔ آپ صلی اللہ علیہ و آلہٖ وسلمنے اپنی تعلیمات سے آگاہی کے لیے عورتوں کے لیے بھی ہفتے میں ایک دن مقرر کیا تھا۔ اس کے علاوہ ازواجِ مطہرات بھی عورتوں کو دین کی باتیں سکھایا کرتی تھیں۔ دانائوں کا قول ہے کہ’’ ایک مردکی تعلیم ایک فردکی تعلیم ہے، جبکہ ایک عورت کی تعلیم ایک خاندان کی تعلیم ہے‘‘ عورت کی آغوش ہی بچے کی پہلی درسگاہ ہے۔ یہ جو کچھ اپنی ماں...

Prognostic Significance of Cellular Iron Metabolism in Breast Cancer

Breast carcinoma is among the most common malignancy in women. Objective: Aim of the present study was to evaluate the prognostic significance of iron expression in the biopsies of patients with breast cancer. Methods: 24 breast biopsies were studied. 19 cases were poorly differentiated, 5 cases were moderately differentiated and there was no well differentiated case. Iron, Estrogen receptor (ER), Progesterone receptor (PR), HER2 and Ki-67 immunohistochemical staining was performed for all these cases. Results: Among the 5 moderately differentiated cases, 3 (60%) were positive for iron staining and among 19 poorly differentiated cases, 11 cases (57.89%) were positive. More iron positive cases (7 out of 14) were triple positive belonging to Luminal B class. Out of 14 iron positive cases, 11 were positive for HER2, 10 for ER, 9 for PR and all positive for Ki-67. Conclusions: Iron deficiency in premenopausal and overload in post-menopausal women can contribute to the development of breast carcinoma. So, iron can be considered as a cheap and effective marker for the prognosis of breast cancer. Association between a risein iron levels and HER2 expression may providenewstrategy for breast cancer treatment.

Myth or Reality: Exploring Teachers Understanding of Teacher Leadership Roles in a Pakistani School

This qualitative case study was designed to explore the teachers' understanding of teacher leadership roles in a Pakistani school. Their understanding of teacher leadership roles were explored in relation to their views, practices and professional roles within the school context. The study was conducted in a school and two female teachers participated in it. The data collection processes involved semi-structured interviews, document analysis and observations inside and outside of the classroom. Their interactions with pedagogy and students inside the classroom and their interactions with parents and colleagues outside the classroom was the focus of observation. The findings indicate the teachers' understanding of teacher leadership roles within the school context, as leading school activities and colleagues was their ultimate goal. The study found that both the teachers continuously improved their personal, interpersonal and professional capacities while interacting with the context. Teachers were found autonomous in their instructional strategies in their respective classrooms. Teachers' instructional leadership roles and their relationship with students were found to be rooted into their personal beliefs of knowledge, learning and experiences. The study also found that teachers' own outlook of students' behaviour and their beliefs about learning determined their own relationship with students. The two teachers defined teacher leadership in a hierarchical fashion. In this vertical order of leadership, the headteacher and teachers with formal roles such as deputy headteacher, coordinators, alternate coordinators and teachers formed the chain of leaders. In this top-down chain of leadership, classroom teachers were placed at the bottom. The study reveals that the teachers viewed parents' involvement crucial for their children education, but their emphasis on parental involvement was limited only to academic affairs. The study also suggests that the scope of leadership of teachers with formal positions (coordinator) is broader and wider than those who possess less formal positions such as alternate coordinator. In short, the teachers' understanding of teacher leadership is different in terms of its scope, but both the teachers understand teachers as leaders. The school context and teachers' early experiences provided them with motivation and opportunities to develop their capacities as teachers and teacher leaders.