Expression Analysis of Sonic Hedgehog in Breast Cancer and its Relationship with Metastasis Involvement of Hedgehog pathway during embryogenesis and mammary development is well known. Salient members of this pathway include SHH, DHH, IHH, PTCH1, SMO and GLI1. Considering high prevalence and early onset of breast cancer among Pakistani population, reactivation of this developmental pathway is hypothesized. In the present study, expression profiling of Hedgehog pathway ligands (SHH, DHH, IHH), mediators (PTCH, SMO) and downstream effector (GLI1) in breast tumorigenesis was explored. The study was divided in two phases. The initial phase included screening of Hedgehog pathway molecules at mRNA and protein levels in Pakistani breast cancer patients. In the second phase, in-vitro models were generated for inhibition of SHH/GLI1 axis. Moreover, effect of SHH/GLI1 inhibition on EMT markers and metastatic cascade was investigated. In the first phase, expression of Hedgehog pathway molecules was evaluated using qRT-PCR and immunohistochemistry in tumor tissues (N=250) and adjacent noncancerous healthy tissues (N=250). SHH, DHH, PTCH1 and GLI1 were significantly overexpressed in tumors compared with respective controls. Significant correlation of SHH, DHH and GLI1 expression with advanced stage, grade, nodal involvement and distant metastasis was observed (p<0.05). Patients having high expression of SHH, DHH and GLI1 demonstrated poor overall survival in the cohort. Overexpression of SHH, DHH and GLI1 was observed to be significantly related with patients having early disease onset and pre-menopausal status. Moreover, Hedgehog pathway was frequently upregulated in luminal B or triple negative breast cancer affected patients. In addition, positive correlation was observed among aforementioned members of the pathway and Ki67 (r-value: 0.63-0.78) emphasizing their role towards disease progression. Expression of Vimentin and Snail was upregulated among SHH/GLI1 positive patients. Strong positive correlation of both Vimentin and Snail with SHH/GLI1 positive patients was observed. On the contrary, E-cadherin was downregulated in SHH/GLI1 positive patients and its correlation with SHH/GLI1 was also negative. xiii In the second phase, SHH knockout models were generated using CRISPR/CAS9 in MDA-MB-231 and MCF-7 cells. Additionally, both cancer cell lines were treated with GANT61 (GLI1 inhibitor) and its effect on cell viability and apoptosis was evaluated using CCK-8 and flow cytometry respectively. Effect of SHH knockout and GANT61 treatment was observed on EMT markers and Akt/ERK using qRT-PCR, western blot analysis and immunofluorescence staining. Invasion and migration assays were performed to investigate influence of SHH/GLI1 suppression on metastatic cascade. Treatment with GANT61 reduced cell viability (p<0.01) and induced apoptosis (p<0.01) in breast cancer cell lines. Expression of Vimentin and Snail was reduced in SHH knockout models and GANT61 treated cells. On the contrary, expression of E-cadherin was increased after inhibition of SHH or GLI1. Suppression of SHH/GLI1 axis also inhibited activation Akt/ ERK as well as reduced migration and invasion capacity in breast cancer cells. Based on these findings, SHH/GLI1 may be used as a prognostic marker in breast cancer patients. Moreover, inhibition of SHH/GLI1 axis provides a novel therapeutic target against aggressive breast cancer subtypes.
والدہ ،مولانا سعیداحمد اکبرآبادی قارئین برہان کویہ معلوم ہوکرصدمہ ہوگا کہ ۲۴؍نومبر کو برادر عزیز مولانا سعیداحمد ایم۔ اے کی والدۂ ماجدہ کاسانحۂ ارتحال پیش آگیا،بڑھاپے کے باوجود ابھی ایسے آثار نہیں پائے جاتے تھے کہ مرحومہ اس قدر جلد پیام اجل کو لبیک کہنے والی ہیں۔ ۱۹؍ نومبر(جمعہ) کی صبح تک بالکل تندرست تھیں۔معمول کے مطابق اپنے اکلوتے بیٹے کے کمرے میں ریڈیو پر کلام پاک سننے کے لیے تشریف لائیں۔قرآن مجید کے بعد نعت سنی، نعت شریف کے بعد مزامیر کے ساتھ سلام شروع ہواتو اسی وقت اٹھ کر اندر چلی گئیں ،بیٹا پکارتا رہا بوا! یہ بھی تو نعت ہی ہے اسے بھی سنتی جاؤ۔بولیں نہیں میاں اس کے ساتھ باجاہے۔ بس یہ آخری گفتگو تھی جو ماں بیٹے میں ہوئی، مولانا سعید احمد کالج چلے گئے۔مشکل سے چند منٹ ہوئے ہوں گے کہ مرحومہ کے جسم کے بائیں حصہ پرفالج کا نہایت خوفناک حملہ ہوا۔اسی وقت بے ہوشی طاری ہوگئی ،مکمل بے ہوشی کی یہ کیفیت آخر وقت تک قائم رہی ،یہاں تک کہ چھٹے روز ۲۴؍ نومبر (چہارشنبہ) کی صبح کوتقریباً ۴ بجے روح جسمِ خاکی سے پرواز کرگئی۔ اناﷲ وانا الیہ راجعون ۔ ان پانچ دنوں میں معالجہ کی بہتر سے بہتر تدبیریں کی گئیں لیکن ساعتِ معین آپہنچی تھی کوئی علاج کامیاب نہیں ہوا اوربالآخر ’’بوا‘‘ ہم سب سے ہمیشہ کے لیے جدا ہوگئیں۔ ’’بوا‘‘ آج دنیا میں نہیں ہیں لیکن ان کے اوصاف ان کے چھوٹوں کوہمیشہ یاد رہیں گے، وہ اول درجہ کی کریم النفس، بااخلاق مرنجان و مرنج خاتون تھیں، عابدہ، معتکفہ، زہدواتقاکاپیکر، خاشعات، متصدقات، صائمات، حافظات، ذاکرات کی پہلی صف میں بیٹھنے والیں، جودوسخا اورشفقت ومودت کابے مثل نمونہ، اکلوتے بیٹے کی شادی اس وقت تک نہیں کی جب تک اپنے ساتھ لے جا کراس کوحج نہیں کرالیا،بیٹا ہونے پرمنت بھی مانی تو کیسی انوکھی۔...
Egyptian society and Indian society faced many social issues, especially during the British colonial rule in the nineteenth and twentieth centuries. The British occupation was an era of decline for the Muslims of the sub-continent. Public minds were not able to recognize this change and did not fully understand the requirements of the time. Writers and poets of that time discussed and dealt with social isues and tried to raise the almost dead community back to life. They wanted their people to be rationalized and to understand the problems of society. Two of those leading writers were Taha Hussein and Deputy Nazir Ahmed. This article will examine Taha Hussein’s role and contribution in raising of Egyptian society and enlightening the Arab minds and also throw light on the efforts of Deputy Nazir Ahmed, a leading social novelist in the sub-continent. The most important issues that were treated through their novels and their writings were the problems and issues of woman and the issue of moral decline in society.
Newcastle disease (ND) is considered as a highly infectious disease of poultry worldwide. The commercial broiler industry is highly susceptible to virulent NDV, the data indicating heavy losses and documentary proof is available on NDV surveillance program. However, a little is known regarding the maintenance and enzootic trends of vNDV infection level in domestic and wild birds. Poor vaccination strategy as well as the existence of virulent form of NDV in the domestic birds indicates a root cause of the occurrence of disease eruption in the developing countries. Here, we report the eleven complete genome sequences of NDV from lovebird parrot (n=1) and exotic parakeets (n=3), backyard chickens (n=5), peacock (n=1) and pheasant (n=1). The complete genome lengths of all isolates were 15,192 nucleotides (nt) with same virulenceassociated cleavage site (112-RRQKRF-117) and selected ones have intracerebral pathogenicity index (ICPI) values ranging from 1.50 to 1.86, which is typical of vNDV. The deduced amino acid residues analyses have shown a number of substitution mutations in the functional domains of fusion and hemagglutinin-neuraminidase proteins. Phylogenetic analysis showed all NDV isolates belong to sub-genotypes VIIi within the genotype VII of class II. The isolation of highly similar viruses (98-99%) during 2011-16 provides the evidence of an epidemiological links between poultry, domestic and wild birds. Our results also support the existence of fifth panzootic as these viruses primarily isolated from South Asia, Middle East and Indonesia and recently spread into Eastern Europe. Active surveillance of these newly emerging viruses to determine their evolution is one of the most realistic strategies for preventing and controlling NDV outbreaks.