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Predictive Role of Cyclooxygenase-2 Expression in Her 2 Neu -Erbb2 Amplified Breast Cancer Patients

Thesis Info

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Author

Um-E-Aban, Muniba

Program

PhD

Institute

Baqai Medical University

City

Karachi

Province

Sindh

Country

Pakistan

Thesis Completing Year

2017

Thesis Completion Status

Completed

Subject

Molecular

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/13482/1/Muniba_um-e-Aban_Molecular_HSR_2017_Baqi_31.07.2018.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676726987821

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Worldwide, a major cause of cancer related deaths in females is breast cancer. Aspirin, a member of the NSAID family of drugs has been indicated by several epidemiological studies to lower the risk for breast cancer especially in hormone receptor positive patients. NSAIDs are known to target the cyclooxygenase enzymes. Two isoforms of COX have been described. COX-1 is inherently expressed in most tissues like gastrointestinal tract, kidney, stomach, platelets and is involved in tissue homeostasis. In contrast, COX-2 is stimuli specific and its expression depends on certain extracellular and intracellular stimuli including mitogens, cytokines, tumour proteins, growth factors. COX-2 has been associated with inflammation and carcinogenesis. It has been observed to be overexpressed in many malignant tumours. COX-2 increases the production of prostaglandin, which inhibits apoptosis, promotes angiogenesis, and induces tumour invasion and metastasis. High COX-2 expression is related to the formation of mammary tumours and is associated with parameters of aggressive breast cancer, like advanced tumour size, grade, lymph node metastasis and HER-2 positive status. The purpose of this study was to investigate the prognostic and predictive role of COX-2 in breast cancer. One hundred and fifty breast cancer paraffin embedded tissue specimens were screened. The age of patients ranged between 30 and 73 years their mean was 42.71 ± 9.4. This study results showed that frequencies of ER+/PR+/HER-2+ were (50.71%) followed by ER-/PR-/HER-2+ (12.7%) ER+/PR-/HER-2- (9.3%) and ER+/PR-/HER-2+ (8.0%). Increased frequency of high grade tumour was noted in luminal B and HER-2+ breast cancer patients. In addition, comparison between HER-2/neu gene amplified and non-amplified groups showed that high grade tumours and ER negative status were more common in HER-2 amplified group. Furthermore, same 150 tissue specimens from the breast cancer patients’ and 101 healthy controls (total 251 female participants) were screened for the functionally important COX-2 SNPs rs 689465, rs 689466 and rs 20417 in its promoter region. Analysis of rs689465, rs689466 and rs20417 was performed by PCR-based restriction fragment length polymorphism. In our study none of these polymorphisms were significantly associated with breast cancer in the single locus analysis. These observations are comparable with other studies that have reported no association of these COX-2 SNPs and breast cancer. However, haplotype G 1195 - A1290 - C 765 (GAC) was found to be associated with breast cancer risk (OR2.90, CI 95% 1.37-6.32 p=0.007). It means that polymorphism in regulatory region of COX-2 may interact in combinational manner. Moreover, GAC was significantly associated with tumour size (OR 5.13, 95% CI 1.140-23.13, p=0.033) and HER-2 status (OR 2.018, 95% CI: 1.061-3.831, p=0.032). In this study, we also observed significant correlation among rs20417CC+GC variants, tumour type (IDC) (P=0.03), ER negativity (P=0.016) and HER-2 positivity (P=0.02), however no association between rs689456, rs689466 and histopathological parameters was observed. On the other hand, in the same breast cancer patients group, in 35 (23%) subjects COX-2 expression was observed by immunohistochemistry (IHC), which showed significant association with HER-2 gene amplification (p = 0.028). In addition, we observed strong association of NF-kB, Akt in 35 HER-2 positive and COX-2 positive breast cancer patients. In summary, we investigated predictive and prognostic role of COX-2, and observed that Akt/NF-kB/COX-2 pathway is an important step in the control of cell survival in HER-2 positive tumour. We suggest that cell signaling mechanisms involving AKT/NF-κB/COX-2 that participates in HER-2 driven suppression of apoptosis requires it to be considered when designing drugs for targeting HER-2 positive tumours.
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ظفر اقبال

حیات و تعلیم:
ظفر اقبال27 ستمبر، 1932ء کو بہاولنگر ، پاکستان میں پیدا ہوئے۔ ان کے والد چک نمبر 49/3Rضلع اوکاڑہ کے ایک معزز زمیندار تھے۔ ظفر اقبال نے ابتدائی تعلیم بہاولنگر سے حاصل کی اور میٹرک ایم سی ہائی اسکول اوکاڑہ سے 1950ء میں کیا۔ انٹرمیڈیٹ کا امتحان ایف سی کالج لاہور اور بی اے گورنمنٹ کالج لاہور سے کیا۔ ظفر اقبال نے ایل ایل بی کا امتحان لا کالج جامعہ پنجاب سے پاس کیا۔
وکالت کا امتحان پاس کرنے کے بعد انہوں نے اوکاڑہ کچہری میں پریکٹس شروع کر دی۔ وہ ایک بار اوکاڑہ ایسوسی ایشن اور دو مرتبہ پریس کلب اوکاڑہ کے صدر بھی رہے۔ اس دوران انہوں نے قومی سیاست میں بھرپور طریقے سے حصہ لیا۔ 1977ء کے انتخابات میں ظفر اقبال نے نیشنل عوامی پارٹی کی طرف سے راؤ خورشید علی خاں (پاکستان پیپلز پارٹی کے نامزد امیدوار) کے مقابلے میں الیکشن لڑا لیکن کامیاب نہ ہو سکے۔
ادبی خدمات:
پرائمری کے دوران ان کی طبیعت شاعری کے لیے موزوں ہو چکی تھی، کیونکہ ان کے استاد نور احمد انجم قریشی جو خود بھی شاعر تھے بچوں کو بطور املا اشعار لکھ کر دیتے۔ ظفر اقبال آٹھویں جماعت تک کلیات میر اور دیوانِ غالب کا بھرپور مطالعہ کر چکے تھے۔ شفیق الرحمن کی تحریریں پڑھ کر ان کے اندر لکھنے کی تحریک پیدا ہوئی۔ انہوں نے غزل کے پیرائے میں فنی اور موضوعاتی سطح پر روایت شکنی کے حوالے سے اپنی ایک الگ اور بھرپور پہچان بنائی۔ اْن کے پہلے شعری مجموعے آب رواں کو عوام اور خواص، ہردو حلقوں میں بے حد پزیرائی ملی۔ اس کے بعد انہوں شعری تجربات کا سلسلہ نہ صرف جاری رکھا بلکہ اسے بام عروج تک پہنچایا۔ 1973ء میں انہوں نے پہلا کالم سرور سکھیرا کے پرچے دھنک کے لیے لکھا۔ ان کے مختلف اخبارات میں...

مقاصد شریعت اور حقوق کی ادائیگی کا باہمی ربط: ایک تحقیقی جائزہ

Allah guided His men through great Prophets and messengers who, through their active economic, religious and politico-economic lives, taught the people how to lead a life. As the people have to come across all these fields of life, therefore, performing rights and duties is essential for a peaceful society. The accomplishment of Sharia objectives depends on the performance of rights and duties. If there is some breach in these rights and duties, the Sharia objectives are lost. If we ponder over the decrees of Allah, it becomes clear that the accomplishment of the decrees itself is the permanence of rights and duties. In this research paper, the rights of the Creator on His men and the rights of men on their Creator, Similarly, the rights of men among themselves and their performance, and the rights of animals and how they can be performed have been described and these Sharia objectives rights are closely related to each other.

Weed Dynamics and Management Studies in Direct Seeded Rice Oryza Sativa L.

Weeds are a stringent biological constraint to direct seeded rice (DSR) growth and yield. Cultural practices can alter the patterns of crop growth and can modify dynamics of weed-crop competition, and hence need to be investigated as a tool for sustainable weed management in DSR. Studies on weed dynamics and their management in DSR sown at different times under different tillage systems were conducted at the Agronomic Research Area, Department of Agronomy, University of Agriculture, Faisalabad over two consecutive growing seasons during summer 2010 and 2011. In Experiment-I, a commonly grown rice (Oryza sativa L.) cultivar Super Basmati was sown on 15th June and 7th July under zero (ZT) and conventional tillage (CT) and was subjected to different durations of weed competition (10, 20, 30, 40, 50 days after sowing [DAS] and weed competition throughout the growing season). Weed free plots were maintained under each tillage system and sowing time for comparison. Experiment-II was also conducted under same tillage systems and sowing times as in Experiment-I, but here the weeds were managed by using pre- and post-emergence herbicides. Pendimethalin and bispyribac sodium at 1137 and 30 g a.i ha-1 were used as pre- or post-emergence application, respectively either alone or in sequence. A weedy check and weed free treatment were included for comparison. Data on weed dynamics (weed types, their density and dry biomass), and rice growth, grain yield and quality characteristics were recorded following standard procedures. Qualitative and quantitative differences were observed in response to two tillage systems, two sowing times, and six weed competition durations. The results showed Poaceae weeds to be more common under ZT while CT had high relative proportion of broad-leaved weeds in total weed density and dry biomass. The density and dry biomass of Cyperaceae weeds was higher in the late sown (on 7th July) crop than early (15th June) sowing. Shifting sowing time of DSR from mid-June to first week of July also reduced weed density but their dry biomass remained unaffected. Tillage systems had no effect on the total weed dry biomass in DSR. Plots subjected to season long weed competition had mostly Poaceae weeds with no broad-leaved weeds being observed at harvest. In the second year of study, the dominance of Poaceae weeds was increased under both tillage systems and sowing times. Significantly less biomass of Poaceae weeds was observed under CT than ZT in 2010; however in 2011, this effect was not observed. Horse purslane (Trianthema portulacastrum L.) and crowfoot grass [Dactyloctenium aegyptium (L.) Willd.] were the dominant broad-leaved and grassy weeds, respectively. Purple nutsedge (Cyperus rotundus L.) was the dominant sedge weed, especially in the July sown crop. Increasing the duration of weed competition increased the time to heading (from 99 to 102 days in 2010 and 98 to 103 days in 2011) while it curtailed time taken from heading to maturity (from 29 to 27 days in 2010 and 29 to 26 days in 2011). Certain growth attributes of DSR were more severely affected in 2011 than in 2010 possibly due to higher weed density and weed biomass. Root length of the DSR crop was decreased by 32% when sowing was delayed from 15th June to 7th July. The DSR crop sown under CT had more root length as well dry biomass than roots produced ZT. A significant interaction was noticed between tillage, sowing time and weed competition duration for the productive tillers during the first year (2010) but not in the second season (2011). The 1000-kernel weight was the same for weed competition durations of 20 to 50 DAS; however, season long weed competition significantly reduced 1000-kernel weight (18.46 to 17.30 g during 2010 and 16.03 to 13.17 g during 2011). Relative grain yield loss (RYL) ranged from 3-13% and 7-16% when weeds were allowed to compete only for 20 DAS. Under season long weed completion, the RYL ranged from 68 to 77% in 2010 and 74 to 80% in 2011. Kernel length and percentage of normal kernels, taken as measures of grain quality were not affected by tillage or sowing time, however, weed competition duration significantly reduced these quality attributes. In addition, increasing the duration of weed competition reduced nitrogen, phosphorus and potassium uptake by the DSR crop in both grains and straw, whereas weed depleted more quantity of these nutrients as the duration of weed competition was extended. In Experiment-II, the highest density of the Poaceae weeds was observed in weedy check plots of ZT or those sown on 15th June during 2010. A sole application of bispyribac sodium did not reduce the density of Poaceae weeds. Plots sown under ZT on 7th July and treated with pendimethalin recorded significantly higher weed density even greater than weedy check during both years. Under ZT, Cyperaceae weeds were at par with the weedy check in the pendimethalin treatment but higher than the weedy check in the July sown DSR crop treated with the same herbicide. Sequential herbicides applications were better than sole application in averting weed growth. For example, the ZT plots sown on 7th July recorded a 56% reduction in weed dry biomass under a sole application of pendimethalin whereas there was an 83% reduction when pendimethalin was followed by bispyribac sodium. Suppression in weed dry biomass achieved in CT plots sown on 15th June with sequential herbicide application was higher (78%) than that of a sole application of pendimethalin (61%) as compared to weedy check. A sole pendimethalin application increased the time taken from sowing to emergence (0.5 days) by the DSR crop. Early heading (1.5 days) was noticed in plots where sequential applications of pre- and post- emergence herbicides were made and these plots also headed at a similar time to the weed free plots. Sequential herbicide applications improved the rice growth attributes over that observed following the sole herbicide application. A sole application of pendimethalin recorded significantly lower grain yield than its sequential application with bispyribac sodium. The sole and sequential chemical weed control treatments increased rice grain and straw nutrient content. The upper and lower most limits for nutrient uptake were noticed in the weed free and weedy check plots, respectively. Sole or sequential herbicide applications were not significantly different from each other regarding nitrogen uptake by weeds yet these treatments were quite effective in preventing nitrogen removal by weeds as compared to weedy check plots. During both years, higher benefit cost ratio (1.91 and 1.92 during 2010 and 2011, respectively) and maximum marginal rate of return (4352 and 3951% during 2010 and 2011, respectively) was associated with the sole application of bispyribac sodium to ZT plots sown in June. Sequential herbicide application was the second most effective treatment in this regard. Weed competition even for 20 DAS reduced grain yields in DSR. Poaceae weeds were much higher under ZT system and were difficult to control with herbicides. Although ZT was cost-effective yet it can only be practiced where an effective chemical weed management strategy can be adopted. A pre-emergence application of pendimethalin with a following post-emergence application of bispyribac sodium was the most effective way to manage weeds in DSR. An early sowing time of 15th June was effective in minimizing weed proliferation and rectifying the yield penalty associated with a later sowing time of 7th July. Therefore, it is concluded that DSR should preferably be sown on 15th June under CT tillage system and weeds must be controlled before 20 DAS to avoid yield loss. For effective weed control within this time frame, sequential herbicide application program comprising of both pre- (pendimethalin) and post-emergence (bispyribac sodium) herbicides should be followed to sustain productivity of DSR. Successful adoption of direct seeding of rice by farmers in Pakistan will depend on whether farmers can control weeds and prevent shifts in weed population from intractable weeds to more difficult-to-control weeds as a consequence of rice direct seeding." xml:lang="en_US