تفسیر بدیع التفاسیر کے فقہی محاسن

Sindh remains a center of great Islamic scholar in early ages till now, scholars of Sindh served in all the fields of Islamic studies. Among Islamic Scholars of Sindh who have left unmatchable repute Sayyed Badi‘ud-Din Shah alR┐shidi, is one of them. He was at home in Quran and its sciences, Hadith and its science, Fiqah and its science. He was author of many books among them was Badi‘ul Taf┐sir, Badi‘ul Taf┐sir (اافتلرس دبعی (currently Contains 11th volumes including excurses (دقمہم (this tafsir adheres to the following sequence: (1) Tafsir of Quran by the Sunnah. (2) Tafsir of Quran by Language. (3) Tafsir of Quran by Opinion. Badi‘ul Tafasir is worthy to get the award of best Sindhi tafsir of this time. In this manuscript it is proved that Badi‘ul Tafasir is best collection of Religious commandments which has been described in detail according to jurisprudential Viewpoints and qualities.

Identification of Therapeutically Important Molecules Against Breast Cancer Cells

Breast cancer is the cancer that develops from breast tissues. Presence of a lump in breast tissue, discharge from the nipple or change in shape, size and color of breast are among the prominent signs of breast cancer.Several factors are responsible in increasing the risk of the development of breast cancer. These include obesity, alcohol uptake, lack of exercise, predisposing genes, and above all, female sex. A number of treatments are used for breast cancer, including chemotherapy, surgery, radiotherapy, and hormonal and targeted therapies. Intravenous chemotherapy which uses cytotoxic drugs is the hallmark of cancer treatment for decades. These cytotoxic agents mainly target rapidly dividing cells, and certain normal cells as well, thereby causing toxicities, such as myelosupression, gastrointestinal symptoms, and hair loss. Significant progress has been made in breast cancer treatment by using systemic agents (non-targeted therapies) and they are still the treatment of choice, despite the appearance of resistance to these treatments. In the recent past, there has been a dramatic shift in cancer therapy, from the use of cytotoxic agents to the development of targeted therapies. This was based on understanding the pathways involved in growth promotion, resistance to apoptosis, and invasive behavior of breast cancer cells. In the past decades, several molecular inhibitors have been identified and tested in clinical trials,that target cancer promoting molecules in cancer cells. Some of the targeted therapies for breast cancer include herceptin, gefitinib, erlotinib, lapatinub, bevacizumab, cetuximab, pertuzumab, etc. These targeted therapies target one or more members of the EGFR family. Apart from using single chemotherapeutic agents, polychemotherapy is also used routinely by offering a survival advantage as compared to single agent therapy. Combination therapies significantly improve the therapeutic outcome because they are administered at suboptimal doses, and thus show less toxicities. The present study was carried out to identify new effective agents against breast cancer cells and also to develop new combination therapies that target specific proteins that serve as oncogenic drivers in breast cancer cells. Our focus was to target tyrosine kinases that serve as signaling molecules for the constitutive proliferation of various cancers, including breast cancer. We selected two breast cancer cell lines for our study i.e. (1) MCF-7, an invasive breast ductal carcinoma cell line expressing estrogen and progesterone receptors, and to a small extent expressing EGFR, and is thus hormone- dependent. (2) MDA-MB-231. It is a cell line that does not express estrogen, progesterone and HER2 receptor, but it overexpresses an EGF dependent EGFR. In the first phase of the study, 1,200 fully characterized compounds were evaluated for their ctotoxicity against both breast cancer cell lines. Compounds showing the most potent activities were further selected for combination studies using three tyrosine kinase inhibitors, imatinib, genistein, and erlotinib, to study the synergistic interactions between the compounds in combination with tyrosine kinase inhibitors. In the second phase, successful synergistic combinations were selected for mechanistic studies. These combinations were tested for their apoptosis inducing potential, and it was found that these combinations significantly enhance the apoptotic death in breast cancer cells, as compared to the test compounds alone. These combinations were further tested for their effects on phosphotyrosylated proteome of the cells. The total phosphotyrosylated proteome was found to be unaffected, except for the diminishing expression in high molecular weight proteins. Based on these observation, the combinations were further tested for their effects on EGFR, and its phosphotyrosylated form (Y-1068). The combination of imatinib with endoperoxides and resveratrol was shown to inhibit the EGFR and P-EGFR expression on MDA-MB-231 cells, while in MCF-7 cells only P-EGFR expression was inhibited. Combination of genistein with one of the endoperoxide (Compound 34) was found to inhibit P-EGFR, but not EGFR in MCF-7 cells. Combination of erlotinib with thiazol derivatives (compounds 10, and 14) resulted in partial inhibition of EGFR, and complete inhibition of P-EGFR in MDA-MB-231 cells.Combination of erlotinib with a pyrimidine derivative (compound 30) resulted in complete inhibition of both EGFR and P-EGFR on MDA-MB-231 cells. Synergistic combinations were tested for their effect on caspases, involved in apoptosis induction of breast cancer cells. It was observed that in MDA-MB-231 cells apoptosis is induced by an intrinsic pathway through the activation of caspases 9 and 3 while in MCF-7 cells, the extrinsic pathway of apoptosis is induced through the activation of caspases 8 and 6. In conclusion, new synergistic combinations targeting EGFR have been identified and deserve to be further investigated in in vivo settings.