Cancer is one the leading reason of mortality worldwide. Resistance to chemotherapy i.e. ‘chemotherapy resistance’ shares the bulk of cancer related mortality. This resistance is mediated by many cellular pathway alterations, ensuing cellular hypoxia being one of the well-known factors. The hypoxic mechanism is driven by various genetic signatures, the most notable among which is hypoxia inducible factor-1α (HIF-1α) which regulates transcription of many genes to promote cancer cell survival, and progression. Multidrug resistance gene-1 (MDR1) and Lysosome-associated protein transmembrane 4B-35 (LAPTM4B-35) are among those notable players which augment their responses to cellular hypoxia. Therefore, pharmacological inhibition of HIF-1 by disrupting its dimerization can be a key strategy to overcome therapy resistance primarily and arresting tumor growth and progression secondarily. This thesis dissertation suggests potential HIF1 dimerization inhibitors constructed through ligand- and structure-based pharmacophore modelling with rigorous virtual database screening. The shortlisted hits then underwent cell line testing under hypoxic conditions for validation of HIF1 inhibition and inhibition of down-stream HIF1 effector gene VEGF and GLUT1.The current work also studied coexpression of hypoxia driven genes HIF-1α, MDR1 and LAPTM4B in peripheral blood lymphocytes of chemotherapy receiving 72 breast, 42 ovarian, 32 colon and 21 prostate cancer patients with reference to their correlation of clinic-pathologic parameters. The current work also proposed structural determinants of LAPTM4B gene computationally for its potential functionality and interaction with cellular proteins of PI3-AKT pathway involved in mediating chemotherapy resistance. The results from the computational and in-vitro validation by western blot analysis identified compound 2 and compound 6 to be effectively disrupting dimerization with concentration of 18.4±14.5 and 274±53.5 µM respectively.The co-expression of HIF-1α, MDR1 and LAPTM4B has been statistically scrutinized via Fisher’s Exact test and the Spearman correlation method. The expression analysis suggested 12–13 folds’ increase in expression of HIF-1α, 2-fold increase in MDR1 and 13–14 fold increase in LAPTM4B mRNA level in peripheral blood of breast, ovarian, prostate and colon cancer patients. In the current study there was an association of HIF-1α, MDR1 and LAPTM4B expression Abstract 2 with advanced tumor stage, metastasis and chemotherapy treated group in breast, ovarian, prostate and colon cancer patients. The Spearman analysis also revealed a positive linear association among HIF-1α, MDR1 and LAPTM4B in all the studied cancer patients. The results from LAPTM4B structural characterization and interaction revealed LAPTM4B interaction with P85α (regulatory domain of PI3K) through its PPRP motif while it interacts with NEDD4 through its PY domain. The important positional interactions are Arg26:LAPTM4B and Glu52:P85α, Arg90:LAPTM4B and Asp21:P85α, Leu348:LAPTM4B and Gly421:NEDD4, Glu362, Tyr351:LAPTM4B and Arg430:NEDD4. The current thesis work proposed potential HIF-1 inhibitors which can be structurally optimized for efficacy, selectivity, pharmacokinetic and toxicity profiling before clinical investigations. The elevated expression of HIF-1α, MDR1 and LAPTM4B in peripheral blood of solid tumor patients can be a predictor of metastasis, disease progression and treatment response in cancers. These interactions of LAPTM4B can aid in drug targeting to design novel LAPTM4B inhibitors.
سہ نثری وہ بھی عجیب پاگل لڑکی تھی جو کتابوں میں پھولوں کی طرح رکھتی تھی میری نثری نظموں ، نثموں کے تراشے ۔۔۔۔۔۔۔ جس نے رقص کرتی ہوائوں کی گرہ کھولی تھی چناب اور نیل کی داستاں سنائی تھی آج وہ صحرا میں آنکھیں نچوڑتا پھرتا ہے ۔۔۔۔۔۔۔ عقیدت سے دیے روشن کرتے ہوئے پوجا کی تھالی میں دل سجا کر مندروں میں داسیاں رقص کرتی رہتی ہیں
Early in 2018, Punjab Assembly passed a law in order to regulate welfare organizations and institutions. All welfare institutions were made bound to a complex official procedure. Violation of this procedure was regarded as a punishable crime. This law was widely discussed in think tanks and was strongly criticized. This research paper deals with understanding of this law, basic sections and their Islamic prespective is analysed according to Sharia. It has been proved in the light of Quran and Sunnah that Islam doesn't permit making non-obligatory charities system so complex and regarding it a crime. Hence, Government should make appropriate reforms in this law while reviewing it.
This dissertation investigates the syllable structure and stress patterns of Sindhi words through the analysis of behavioral data from speech judgment experiments, and of acoustic data from speech production experiments, conducted with native speakers of Sindhi. There were three basic queries, the first of which was: What is the syllable structure? For this, a syllable judgment study was designed to explore syllable structure in Sindhi indigenous words and English loanwords. Syllable counts and syllabification judgments were elicited from native speakers for words presented in written format. This syllable judgment study sought to determine native speakers’ intuitions about the syllabification of Sindhi words in terms of the major principles: Sonority Sequencing Principle (SSP) and Maximal Onset Principle (MOP) of syllabification, and phonotactic constraints of the language, referencing to consonant clusters syllable-initially, -medially, and -finally. On the basis of the data, the study devised an algorithm for syllabification that illustrates how a Sindhi word is syllabified. Secondly, it investigates the word-level stress patterns in Sindhi and identifies the phonological factors that determine stress location in polysyllabic words. This study also examines the intuition of native speakers by eliciting their judgments about the location of lexical stress in words of two, three, four and five syllables from 150 selected words. The findings from the stress judgment study shows that native speakers have a preference for identifying stress on a heavy syllable. This pattern is strongest in words that have a single heavy syllable. In words with multiple heavy syllables the pattern is less clear. In tri-syllabic words there appears to be a preference for stress on the leftmost heavy syllable, while four-syllable words do not show this pattern as clearly. However, five-syllable words, show a preference for lexical stress on the penultimate syllable, which does not seem to depend on syllable weight. From these data the study concludes that Sindhi is not a fixed stress language. The location of stress varies in words according to the weight of the syllables in the word. This study concludes that Sindhi is a weak quantity-sensitive language and it is not a fixed stress language. Third question investigated here is what are the acoustic correlates of word level stress in Sindhi? This work collects and examines quantitative acoustic data (2000 voice samples of Sindhi speech) from ten native speakers. From the physical examination of stressed and unstressed vocalic sounds, the study found strong evidence that several phonetic properties are altered by word-level stress in Sindhi. The speech materials used in the acoustic analysis are ten minimal stress pairs of words that differ primarily in the location of stress (first vs. second syllable). The test words were all highly familiar words selected and chosen to minimize segmental variation among the words. The acoustic analysis of productions of these 20 words is based on measures of fundamental frequency (F0), vowel formants (F1 and F2) as a measure of vowel quality and vowel duration. In addition, the stop closure duration of the word-initial onset consonant for stressed and unstressed syllables was also measured. The results show strong evidence that stressed syllables have higher F0, F1 and F2, and greater duration values as compared to unstressed syllables. In addition, the study undertook another experiment of preliminary intonational aspects of Sindhi in order to investigate the role of pitch between stress and intonation of contrastive focus accentual phrase in Sindhi, F0 of vowel pitch contours were analyzed for evidence that the location of the beginning of the pitch rise, or the pitch peak varies in relation to the location of the stressed syllable in the word. Sindhi pitch accent rises from the first syllable in disyllable words, irrespective of syllable weight, and the rise is followed by a fall at end of the word. Thus, it was observed, there was a rise and fall in intonation of contrastive focus accentual phrase. A peak occurs on the second or third syllable and may span over two syllables in longer words.