Despite advances in the molecular sub-classification and risk-stratification of medulloblastoma (... more Despite advances in the molecular sub-classification and risk-stratification of medulloblastoma (MB), a subset of tumours remain refractory to current multimodal therapies. Group 3 (MBGroup3) patients represent around 25% of MBs, and amplification and elevated expression of MYC in this group correlates with dismal clinical outcomes. Since direct targeting of MYC remains elusive, understanding and exploiting metabolic dependencies in MYC-amplified MBGroup3 may reveal novel therapeutic opportunities. We engineered three independent regulable MYC-amplified MBGroup3 cell-based models, each harbouring doxycycline-inducible anti-MYC shRNAs (two independent species) or a non-silencing shRNA control. In all three models, MYC knockdown (KD) revealed persistent MYC-dependent cancer phenotypes, reduction in proliferation and cell cycle progression. We utilised 1H high-resolution magic angle spectroscopy (HRMAS) and stable isotope-resolved metabolomics to assess changes in intracellular metabol...
In present education system, out-of-balance life of student is one of the prominent challenges. S... more In present education system, out-of-balance life of student is one of the prominent challenges. Students are mostly getting educated to posses' good packages, positions, status or achieving academic excellence. They are not investing time and effort to achieve balance and joy in their personal and family life. The 20 to 25 years of education if not making a person with a definite human conduct then we should re-evaluate and rethink the purpose and need of such education system. Education is not just learning skills, getting degrees but it is to rightly understand the essence of living and to live in coexistence with each entity of the cosmos. Life of passion, purpose and joy seems to be missing in campuses of educational institutes. Inspiration from nature where coexistence of cosmos entities is observed could guide us to develop holistic education system. Such system could ensure balance in student's personal life and harmony among all individuals of education system. This ...
Background Cholecystokinin and gastrin are endocrine growths factors for certain tumours and CCK ... more Background Cholecystokinin and gastrin are endocrine growths factors for certain tumours and CCK R and CCK R receptors are ideal molecular targets for novel smart chemo therapeutics with a beneficial overall profile due to their anxiolytic and antidepressant properties Lung cancers are fuelled by gastrin and therefore selective gastrin CCK R antagonists are ideal experimental drug candidates Objective Synthesis and evaluation of novel CCK antagonists most preferred CCK gastrin selective for the treatment of lung cancers Methods A fast and efficient synthesis of hydroxy pyrrolones in steps from renewable biomass was performed After initial radiolabelled receptor binding studies with hot CCK subsequent in vitro evaluation with isolated duodenum preparations confirmed CCK antagonism Cell based studies using the MTT assay provided a candidate for in vivoxenograft models with nude mice Rational drug design was supported by molecular modelling experiments Results Potent and selective CCK ...
Please find attached the report titled "Green labs-Energy Management" for your review. The projec... more Please find attached the report titled "Green labs-Energy Management" for your review. The project was conducted during our course numbered CHBE 484 titled Green engineering. The group consisted of Mankaran Singh, Abin Antony and Shruti Kapoor. Currently, many research labs on campus use older outdated equipment that take into account minimal considerations for energy usage. This project examines the impact of older, less energy efficient equipment and analyses the equipment to see if replacement, maintenance or nothing should be done with the various equipments. This project was conducted with the aim of reducing the green house gas emissions, while keeping cost in mind. The findings from this project have been enclosed and presented in this document below. This project would not have been possible if it were not for help from both staff in the Chemical and Biological Engineering building and the U.B.C sustainability office and we would like to extend a sincere thanks for all their patience and help.
Outcomes for adult patients with acute lymphoblastic leukemia (ALL) are dismal and have not kept ... more Outcomes for adult patients with acute lymphoblastic leukemia (ALL) are dismal and have not kept pace with their pediatric counterparts, with five-year survival rates of less than 45%. TP53 mutations are infrequent in ALL, but activity of the oncoprotein MDM2 may otherwise phenotypically disrupt and circumvent normal p53 function, positing the p53-MDM2 signaling axis as a potential therapeutic target for the engagement of intrinsic cell death programs. Given the clinical safety and responses to p53-MDM2 antagonist idasanutlin (RG7388) in other hematological cancers and solid tumors, we aimed to evaluate the therapeutic potential of idasanutlin in ALL. Single-agent activity of idasanutlin was investigated in 17 high-risk ALL patient and patient-derived xenograft samples (aged 4 to 51 years), both B-ALL (n=15) and T-ALL (n=2), including KMT2A-rearranged, TCF3-rearranged, and Philadelphia-positive ALL. An ex vivo coculture of ALL blasts and hTERT-immortalized mesenchymal stem cells (MS...
Leukaemia cells re-program their microenvironment to provide proliferation support and protection... more Leukaemia cells re-program their microenvironment to provide proliferation support and protection from standard chemotherapy, molecularly targeted therapies, and immunotherapy. Although much is becoming known about molecules that drive niche-dependent treatment resistance; means of targeting these in the clinics has remained a key obstacle. To address this challenge, we have developed human induced pluripotent stem cell engineered nichesex vivoto reveal insights into druggable cancer-niche dependencies. We show that mesenchymal (iMSC) and vascular niche-like (iANG) cells supportex vivoproliferation of patient-derived leukaemia cells, impact dormancy and mediate therapy resistance. iMSC protected both non-cycling and cycling blasts against dexamethasone treatment while iANG protected only dormant blasts. Leukaemia proliferation and protection from dexamethasone induced-apoptosis was dependent on direct cell-cell contact and mediated by CDH2. To explore the therapeutic potential of di...
Fast disintegrating tablets (FDTs) have received ever-increasing demand during the last decade an... more Fast disintegrating tablets (FDTs) have received ever-increasing demand during the last decade and the field has become a rapidly growing area in the pharmaceutical industry. Fast disintegrating tablets (FDTs) are those solid dosage forms when put on tongue, disintegrate or dissolve instantaneously, releasing the drug, within a few seconds without the need of water. Fast disintegrating tablets (FDTs) aim for designing dosage forms, convenient to be manufactured and administered, free of side effects, offering immediate release and enhanced bioavailability, to achieve better patient compliance. Fast disintegrating tablets have been formulated for p ediatric, geriatric, and bedridden patients and for active patients who are busy and traveling and may not have access to water. Such formulations provide an opportunity for product life extension in the many elderly persons which have difficulty in taking conventional oral dosage form (viz., solutions, suspensions, tablets, and capsules) because of hand tremors and dysphagia. The current article is focused on ideal requirements, need for development of FDTs, challenges in formulation, suitability of drug candidates, superdisintegrants employed, various technologies developed for FDTs, patented technologies like Wowtab, Durasolv, Orasolv, Flashtab, Zydis, Frosta technology, Sheaform, Ceaform technology, Nanocrystal technology which have gained importance in international market, evaluation methods and various marketed products.
Recent Patents on Drug Delivery & Formulation, 2020
Background: Dental caries originate due to the localized dissolution of the hard tissues of teeth... more Background: Dental caries originate due to the localized dissolution of the hard tissues of teeth, mainly caused by acids, developed by the presence of microorganisms in the biofilm (dental plaque) on the surface of teeth causing “cavities”. Commercially available liquid mouthwashes containing synthetic active ingredients possess limitations like teeth staining, higher alcoholic content, taste disturbances, xerostomia, and stability issues. Objective: To make the solid preparation for oral hygiene (US6428770B1) in the form of herbal effervescent mouthwash tablet (CN106619318A, US8728446B2) using Azadirachta indica and Curcumin having antimicrobial, antibacterial, antiplaque, and anti-inflammatory activity. Methods: The optimization study of effervescent granules was performed by 33 factorial design. A total of 27 preliminary experimental batches were prepared by the fusion method, varying the amount of citric acid, tartaric acid, and sodium bicarbonate. A complex of curcumin was pre...
Nanotechnology has achieved the status as one of the vital research endeavors of 21 st century, w... more Nanotechnology has achieved the status as one of the vital research endeavors of 21 st century, which may be called as "Nano-Century" with nanotechnology making its presence felt in different spheres of lives. Nanotechnology may be defined as the creation of materials, drugs and devices that are used to manipulate matter of size in the range of 1-100nm. Nanotechnology has found its applications in many fields related to medicine including novel drug delivery systems. Many different types of nanosystems have been utilized in diagnostics and therapeutics of various diseases. To subside the disadvantages of conventional cancer therapeutics, nanotechnology has been given considerable attention. The purpose of this expert review is to discuss the impact of nanotechnology in the treatment of the cancer. These have been applied to improve drug delivery and to overcome some of the problems of drug delivery in cancer. Current nanotechnology platforms for cancer therapeutics encompass a vast array of nanomaterials and nanodevices. This review will focus on seven of the most prominent and most widely studied: polymeric nanoparticles, nanoshells, carbon nanotubes, dendrimers, quantum dots, superparamagnetic nanoparticles, and liposomes. All of these nanotechnology platforms can be multifunctional, so they are frequently touted as "smart" or "intelligent." It is concluded how nanotechnology can help solve one of the most challenging and longstanding problems in medicine, which is how to eliminate cancer without harming normal body tissue.
Acute lymphoblastic leukemia (ALL) is the most common type of childhood leukaemia. Recently impro... more Acute lymphoblastic leukemia (ALL) is the most common type of childhood leukaemia. Recently improved risk stratification resulted in therapy optimization and extended survival for the majority of cases. Unfortunately, there is still a significant number of patients either relapsing or not responding to treatment with response to glucocorticoids being one of the most important prognostic indicators of treatment outcome. In order to investigate the mechanism of dexamethasone resistance, we performed genome-wide CRISPR screens in patient derived xenotransplant (PDX) material from t(17;19)-positive ALL. Primary material was obtained from the patient at the presentation and at relapse stage of disease and corresponding PDX samples were generated in immunocompromised NSG mice. PDX cells were lentivirally transduced with the CRISPR knockout pooled 'Brunello' library and then subjected to dexamethasone pressure both ex vivo and in vivo. For the in vivo screen, CRISPR-modified cells ...
Background: Cholecystokinin and gastrin are endocrine growths factors for certain tumours and CCK... more Background: Cholecystokinin and gastrin are endocrine growths factors for certain tumours and CCK 1 R and CCK2R receptors are ideal molecular targets for novel smart chemotherapeutics with a beneficial overall profile due to their anxiolytic and antidepressant properties. Lung cancers are fuelled by gastrin and therefore, selective gastrin (CCK 2 R) antagonists are ideal experimental drug candidates. Objective: Synthesis and evaluation of novel CCK antagonists, most preferred CCK 2 / gastrin selective for the treatment of lung cancers. Methods: A fast and efficient synthesis of hydroxy-pyrrolones in 2 steps from renewable biomass was performed. After initial radiolabelled receptor binding studies with hot CCK8, subsequent in vitro evaluation with isolated duodenum preparations confirmed CCK antagonism. Cell based studies using the MTT assay provided a candidate for in vivo xenograft models with nude mice. Rational drug design was supported by molecular modelling experiments. Results: Potent and selective CCK antagonists were prepared as stable crystalline materials in high yields. Gastrin antagonists were in vitro active on isolated tissue preparations and inhibited breast, colon and lung cancer cell lines in vitro with IC 50 to 45nM for the privileged hydroxyl-pyrrolone lead structure in the MTT assay for human cancer cell lines. PNB-101, a fluorinated 5-hydroxy-5-aryl-pyrrol-2-one, gave up to 80% inhibition of tumour growths by oral administration in athymic mice transplanted with the human lung cancer cell line H727. Conclusion: PNB-101 is a potential chemotherapeutic agent for CCK-gastrin related cancers and entered preclinical development.
Dietary habits have been associated with variations in the risk of colon disorders, either its in... more Dietary habits have been associated with variations in the risk of colon disorders, either its increase or decrease. Colon-specific approaches showed their potential to target and treat colon cancers and inflammatory diseases, but they vary in success rates for local recurrence, disease-free survival, and overall survival. Also, chemotherapies and radiotherapies have been applied as the surgical adjuvant treatments. The significant role of exogenously administered Lactobacilli in reducing toxin-producing bacteria in the gut and increases the longevity of the host, led to the coining of the term 'probiotics'. The evidence on the effects of inulin and oligofructose on colonization, translocation of pathogens and the prevention of intestinal diseases make them suitable candidates to treat colon disorders. Among potentially protective foods, growing attention has been dedicated to functional foods comprising probiotics, such as Lactobacilli or Bifidobacteria, and prebiotics such as fructooligosaccharides or fructans, as their consumption may treat inflammatory bowel diseases, like ulcerative colitis, crohn's disease as well as experimentally induced colon cancer in mammals. The readily apparent synergy of concomitantly using beneficial microorganisms and nutritive materials that support their growth led to the term "synbiotics" to describe foods or supplements that combine both probiotics and prebiotics. Various potential mechanisms are addressed in the present paper. This article discusses the real value of dietary components, which offers practical information to help patients as well as health professionals. Furthermore, article has focused on the possible value of probiotics, prebiotics and synbiotics in treatment and maintenance therapy of colonic ailments.
Acceptability of any dosage form are mainly depends over its taste i.e. mouth feel. Drug molecule... more Acceptability of any dosage form are mainly depends over its taste i.e. mouth feel. Drug molecule interacts with taste receptor on the tongue to give bitter, sweet or salty taste sensation, when they dissolve in saliva. This sensation of the taste is the result of signal transduction from the receptor organs for taste, commonly known as taste buds. In market, there are numbers of pharmaceutical preparations available in which actives are bitter in taste. The improved palatability in these products has prompted the development of numerous formulations, which improved performance and acceptability. The bitterness of preparation also leads to patient incompliance. So masking of bitterness becomes essential. To overcome this problem, many techniques have been developed to mask the bitter taste of drugs. These techniques are not only mask the bitter taste of drug but also enhance the bioavailability and performance of drug dosage form. It includes adding sugars, flavors, sweeteners, use ...
Conventional drug delivery systems are known to provide an immediate release of drug, in which on... more Conventional drug delivery systems are known to provide an immediate release of drug, in which one can not control the release of the drug and can not maintain effective concentration at the target site forlonger time. Osmotically controlled drug delivery systems (OCDDS) are most promising systems for controlleddrug delivery. Osmotically controlled drug delivery systems utilize osmotic pressure for controlled delivery ofactive agents. Various patents are available for osmotic drug delivery system like Rose and Nelson pump,Higuchi Leeper pump, Higuchi Theeuwes pump, Elementary osmotic pump etc. Various techniques available for preparation of OCDDS include push pull osmotic pump, Osmotic bursting osmotic pump, Liquid OROS,Telescopic capsule for delayed release, OROS-CT (colon targeting), and Sandwiched osmotic tablet system.These systems can be used for systemic as well as targeted delivery of drugs. Drug delivery from these systems,to a large extent, is independent of physiological f...
Mucoadhesion is a field of current interest in the design of drug delivery systems. Mucoadhesion ... more Mucoadhesion is a field of current interest in the design of drug delivery systems. Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface. Mucoadhesive drug delivery system may be designed to enable prolonged residence time of the dosage form at the site of application or absorption and facilitate an intimate contact of the dosage form with the underline absorption surface. Extending the residence time of a dosage form at a particular site and controlling the release of drug from the dosage form are useful especially for achieving controlled plasma level of the drug as well as improving bioavailability. Application of these dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that undergo acid degradation or extensive first-pass metabolism. The present review describes mucoadhesion, mucoadhesive polymers and use of these polymers in designing different types of ...
Various minerals have been reported which are directly linked to our health and cancer developmen... more Various minerals have been reported which are directly linked to our health and cancer development in body. The immune system (immunoglobulin's, cell mediated immunity, phagocytosis complement, lysosomes, interferon, metabolic function, hormones, metabolic and respiratory alkalosis) is the natural mechanism which defends against cancer. Minerals like zinc, selenium, magnesium, vanadium, and germanium augment this natural mechanism. In this review various aspects of these mineral are discussed and their relation with cancer.
Despite advances in the molecular sub-classification and risk-stratification of medulloblastoma (... more Despite advances in the molecular sub-classification and risk-stratification of medulloblastoma (MB), a subset of tumours remain refractory to current multimodal therapies. Group 3 (MBGroup3) patients represent around 25% of MBs, and amplification and elevated expression of MYC in this group correlates with dismal clinical outcomes. Since direct targeting of MYC remains elusive, understanding and exploiting metabolic dependencies in MYC-amplified MBGroup3 may reveal novel therapeutic opportunities. We engineered three independent regulable MYC-amplified MBGroup3 cell-based models, each harbouring doxycycline-inducible anti-MYC shRNAs (two independent species) or a non-silencing shRNA control. In all three models, MYC knockdown (KD) revealed persistent MYC-dependent cancer phenotypes, reduction in proliferation and cell cycle progression. We utilised 1H high-resolution magic angle spectroscopy (HRMAS) and stable isotope-resolved metabolomics to assess changes in intracellular metabol...
In present education system, out-of-balance life of student is one of the prominent challenges. S... more In present education system, out-of-balance life of student is one of the prominent challenges. Students are mostly getting educated to posses' good packages, positions, status or achieving academic excellence. They are not investing time and effort to achieve balance and joy in their personal and family life. The 20 to 25 years of education if not making a person with a definite human conduct then we should re-evaluate and rethink the purpose and need of such education system. Education is not just learning skills, getting degrees but it is to rightly understand the essence of living and to live in coexistence with each entity of the cosmos. Life of passion, purpose and joy seems to be missing in campuses of educational institutes. Inspiration from nature where coexistence of cosmos entities is observed could guide us to develop holistic education system. Such system could ensure balance in student's personal life and harmony among all individuals of education system. This ...
Background Cholecystokinin and gastrin are endocrine growths factors for certain tumours and CCK ... more Background Cholecystokinin and gastrin are endocrine growths factors for certain tumours and CCK R and CCK R receptors are ideal molecular targets for novel smart chemo therapeutics with a beneficial overall profile due to their anxiolytic and antidepressant properties Lung cancers are fuelled by gastrin and therefore selective gastrin CCK R antagonists are ideal experimental drug candidates Objective Synthesis and evaluation of novel CCK antagonists most preferred CCK gastrin selective for the treatment of lung cancers Methods A fast and efficient synthesis of hydroxy pyrrolones in steps from renewable biomass was performed After initial radiolabelled receptor binding studies with hot CCK subsequent in vitro evaluation with isolated duodenum preparations confirmed CCK antagonism Cell based studies using the MTT assay provided a candidate for in vivoxenograft models with nude mice Rational drug design was supported by molecular modelling experiments Results Potent and selective CCK ...
Please find attached the report titled "Green labs-Energy Management" for your review. The projec... more Please find attached the report titled "Green labs-Energy Management" for your review. The project was conducted during our course numbered CHBE 484 titled Green engineering. The group consisted of Mankaran Singh, Abin Antony and Shruti Kapoor. Currently, many research labs on campus use older outdated equipment that take into account minimal considerations for energy usage. This project examines the impact of older, less energy efficient equipment and analyses the equipment to see if replacement, maintenance or nothing should be done with the various equipments. This project was conducted with the aim of reducing the green house gas emissions, while keeping cost in mind. The findings from this project have been enclosed and presented in this document below. This project would not have been possible if it were not for help from both staff in the Chemical and Biological Engineering building and the U.B.C sustainability office and we would like to extend a sincere thanks for all their patience and help.
Outcomes for adult patients with acute lymphoblastic leukemia (ALL) are dismal and have not kept ... more Outcomes for adult patients with acute lymphoblastic leukemia (ALL) are dismal and have not kept pace with their pediatric counterparts, with five-year survival rates of less than 45%. TP53 mutations are infrequent in ALL, but activity of the oncoprotein MDM2 may otherwise phenotypically disrupt and circumvent normal p53 function, positing the p53-MDM2 signaling axis as a potential therapeutic target for the engagement of intrinsic cell death programs. Given the clinical safety and responses to p53-MDM2 antagonist idasanutlin (RG7388) in other hematological cancers and solid tumors, we aimed to evaluate the therapeutic potential of idasanutlin in ALL. Single-agent activity of idasanutlin was investigated in 17 high-risk ALL patient and patient-derived xenograft samples (aged 4 to 51 years), both B-ALL (n=15) and T-ALL (n=2), including KMT2A-rearranged, TCF3-rearranged, and Philadelphia-positive ALL. An ex vivo coculture of ALL blasts and hTERT-immortalized mesenchymal stem cells (MS...
Leukaemia cells re-program their microenvironment to provide proliferation support and protection... more Leukaemia cells re-program their microenvironment to provide proliferation support and protection from standard chemotherapy, molecularly targeted therapies, and immunotherapy. Although much is becoming known about molecules that drive niche-dependent treatment resistance; means of targeting these in the clinics has remained a key obstacle. To address this challenge, we have developed human induced pluripotent stem cell engineered nichesex vivoto reveal insights into druggable cancer-niche dependencies. We show that mesenchymal (iMSC) and vascular niche-like (iANG) cells supportex vivoproliferation of patient-derived leukaemia cells, impact dormancy and mediate therapy resistance. iMSC protected both non-cycling and cycling blasts against dexamethasone treatment while iANG protected only dormant blasts. Leukaemia proliferation and protection from dexamethasone induced-apoptosis was dependent on direct cell-cell contact and mediated by CDH2. To explore the therapeutic potential of di...
Fast disintegrating tablets (FDTs) have received ever-increasing demand during the last decade an... more Fast disintegrating tablets (FDTs) have received ever-increasing demand during the last decade and the field has become a rapidly growing area in the pharmaceutical industry. Fast disintegrating tablets (FDTs) are those solid dosage forms when put on tongue, disintegrate or dissolve instantaneously, releasing the drug, within a few seconds without the need of water. Fast disintegrating tablets (FDTs) aim for designing dosage forms, convenient to be manufactured and administered, free of side effects, offering immediate release and enhanced bioavailability, to achieve better patient compliance. Fast disintegrating tablets have been formulated for p ediatric, geriatric, and bedridden patients and for active patients who are busy and traveling and may not have access to water. Such formulations provide an opportunity for product life extension in the many elderly persons which have difficulty in taking conventional oral dosage form (viz., solutions, suspensions, tablets, and capsules) because of hand tremors and dysphagia. The current article is focused on ideal requirements, need for development of FDTs, challenges in formulation, suitability of drug candidates, superdisintegrants employed, various technologies developed for FDTs, patented technologies like Wowtab, Durasolv, Orasolv, Flashtab, Zydis, Frosta technology, Sheaform, Ceaform technology, Nanocrystal technology which have gained importance in international market, evaluation methods and various marketed products.
Recent Patents on Drug Delivery & Formulation, 2020
Background: Dental caries originate due to the localized dissolution of the hard tissues of teeth... more Background: Dental caries originate due to the localized dissolution of the hard tissues of teeth, mainly caused by acids, developed by the presence of microorganisms in the biofilm (dental plaque) on the surface of teeth causing “cavities”. Commercially available liquid mouthwashes containing synthetic active ingredients possess limitations like teeth staining, higher alcoholic content, taste disturbances, xerostomia, and stability issues. Objective: To make the solid preparation for oral hygiene (US6428770B1) in the form of herbal effervescent mouthwash tablet (CN106619318A, US8728446B2) using Azadirachta indica and Curcumin having antimicrobial, antibacterial, antiplaque, and anti-inflammatory activity. Methods: The optimization study of effervescent granules was performed by 33 factorial design. A total of 27 preliminary experimental batches were prepared by the fusion method, varying the amount of citric acid, tartaric acid, and sodium bicarbonate. A complex of curcumin was pre...
Nanotechnology has achieved the status as one of the vital research endeavors of 21 st century, w... more Nanotechnology has achieved the status as one of the vital research endeavors of 21 st century, which may be called as "Nano-Century" with nanotechnology making its presence felt in different spheres of lives. Nanotechnology may be defined as the creation of materials, drugs and devices that are used to manipulate matter of size in the range of 1-100nm. Nanotechnology has found its applications in many fields related to medicine including novel drug delivery systems. Many different types of nanosystems have been utilized in diagnostics and therapeutics of various diseases. To subside the disadvantages of conventional cancer therapeutics, nanotechnology has been given considerable attention. The purpose of this expert review is to discuss the impact of nanotechnology in the treatment of the cancer. These have been applied to improve drug delivery and to overcome some of the problems of drug delivery in cancer. Current nanotechnology platforms for cancer therapeutics encompass a vast array of nanomaterials and nanodevices. This review will focus on seven of the most prominent and most widely studied: polymeric nanoparticles, nanoshells, carbon nanotubes, dendrimers, quantum dots, superparamagnetic nanoparticles, and liposomes. All of these nanotechnology platforms can be multifunctional, so they are frequently touted as "smart" or "intelligent." It is concluded how nanotechnology can help solve one of the most challenging and longstanding problems in medicine, which is how to eliminate cancer without harming normal body tissue.
Acute lymphoblastic leukemia (ALL) is the most common type of childhood leukaemia. Recently impro... more Acute lymphoblastic leukemia (ALL) is the most common type of childhood leukaemia. Recently improved risk stratification resulted in therapy optimization and extended survival for the majority of cases. Unfortunately, there is still a significant number of patients either relapsing or not responding to treatment with response to glucocorticoids being one of the most important prognostic indicators of treatment outcome. In order to investigate the mechanism of dexamethasone resistance, we performed genome-wide CRISPR screens in patient derived xenotransplant (PDX) material from t(17;19)-positive ALL. Primary material was obtained from the patient at the presentation and at relapse stage of disease and corresponding PDX samples were generated in immunocompromised NSG mice. PDX cells were lentivirally transduced with the CRISPR knockout pooled 'Brunello' library and then subjected to dexamethasone pressure both ex vivo and in vivo. For the in vivo screen, CRISPR-modified cells ...
Background: Cholecystokinin and gastrin are endocrine growths factors for certain tumours and CCK... more Background: Cholecystokinin and gastrin are endocrine growths factors for certain tumours and CCK 1 R and CCK2R receptors are ideal molecular targets for novel smart chemotherapeutics with a beneficial overall profile due to their anxiolytic and antidepressant properties. Lung cancers are fuelled by gastrin and therefore, selective gastrin (CCK 2 R) antagonists are ideal experimental drug candidates. Objective: Synthesis and evaluation of novel CCK antagonists, most preferred CCK 2 / gastrin selective for the treatment of lung cancers. Methods: A fast and efficient synthesis of hydroxy-pyrrolones in 2 steps from renewable biomass was performed. After initial radiolabelled receptor binding studies with hot CCK8, subsequent in vitro evaluation with isolated duodenum preparations confirmed CCK antagonism. Cell based studies using the MTT assay provided a candidate for in vivo xenograft models with nude mice. Rational drug design was supported by molecular modelling experiments. Results: Potent and selective CCK antagonists were prepared as stable crystalline materials in high yields. Gastrin antagonists were in vitro active on isolated tissue preparations and inhibited breast, colon and lung cancer cell lines in vitro with IC 50 to 45nM for the privileged hydroxyl-pyrrolone lead structure in the MTT assay for human cancer cell lines. PNB-101, a fluorinated 5-hydroxy-5-aryl-pyrrol-2-one, gave up to 80% inhibition of tumour growths by oral administration in athymic mice transplanted with the human lung cancer cell line H727. Conclusion: PNB-101 is a potential chemotherapeutic agent for CCK-gastrin related cancers and entered preclinical development.
Dietary habits have been associated with variations in the risk of colon disorders, either its in... more Dietary habits have been associated with variations in the risk of colon disorders, either its increase or decrease. Colon-specific approaches showed their potential to target and treat colon cancers and inflammatory diseases, but they vary in success rates for local recurrence, disease-free survival, and overall survival. Also, chemotherapies and radiotherapies have been applied as the surgical adjuvant treatments. The significant role of exogenously administered Lactobacilli in reducing toxin-producing bacteria in the gut and increases the longevity of the host, led to the coining of the term 'probiotics'. The evidence on the effects of inulin and oligofructose on colonization, translocation of pathogens and the prevention of intestinal diseases make them suitable candidates to treat colon disorders. Among potentially protective foods, growing attention has been dedicated to functional foods comprising probiotics, such as Lactobacilli or Bifidobacteria, and prebiotics such as fructooligosaccharides or fructans, as their consumption may treat inflammatory bowel diseases, like ulcerative colitis, crohn's disease as well as experimentally induced colon cancer in mammals. The readily apparent synergy of concomitantly using beneficial microorganisms and nutritive materials that support their growth led to the term "synbiotics" to describe foods or supplements that combine both probiotics and prebiotics. Various potential mechanisms are addressed in the present paper. This article discusses the real value of dietary components, which offers practical information to help patients as well as health professionals. Furthermore, article has focused on the possible value of probiotics, prebiotics and synbiotics in treatment and maintenance therapy of colonic ailments.
Acceptability of any dosage form are mainly depends over its taste i.e. mouth feel. Drug molecule... more Acceptability of any dosage form are mainly depends over its taste i.e. mouth feel. Drug molecule interacts with taste receptor on the tongue to give bitter, sweet or salty taste sensation, when they dissolve in saliva. This sensation of the taste is the result of signal transduction from the receptor organs for taste, commonly known as taste buds. In market, there are numbers of pharmaceutical preparations available in which actives are bitter in taste. The improved palatability in these products has prompted the development of numerous formulations, which improved performance and acceptability. The bitterness of preparation also leads to patient incompliance. So masking of bitterness becomes essential. To overcome this problem, many techniques have been developed to mask the bitter taste of drugs. These techniques are not only mask the bitter taste of drug but also enhance the bioavailability and performance of drug dosage form. It includes adding sugars, flavors, sweeteners, use ...
Conventional drug delivery systems are known to provide an immediate release of drug, in which on... more Conventional drug delivery systems are known to provide an immediate release of drug, in which one can not control the release of the drug and can not maintain effective concentration at the target site forlonger time. Osmotically controlled drug delivery systems (OCDDS) are most promising systems for controlleddrug delivery. Osmotically controlled drug delivery systems utilize osmotic pressure for controlled delivery ofactive agents. Various patents are available for osmotic drug delivery system like Rose and Nelson pump,Higuchi Leeper pump, Higuchi Theeuwes pump, Elementary osmotic pump etc. Various techniques available for preparation of OCDDS include push pull osmotic pump, Osmotic bursting osmotic pump, Liquid OROS,Telescopic capsule for delayed release, OROS-CT (colon targeting), and Sandwiched osmotic tablet system.These systems can be used for systemic as well as targeted delivery of drugs. Drug delivery from these systems,to a large extent, is independent of physiological f...
Mucoadhesion is a field of current interest in the design of drug delivery systems. Mucoadhesion ... more Mucoadhesion is a field of current interest in the design of drug delivery systems. Mucoadhesion is commonly defined as the adhesion between two materials, at least one of which is a mucosal surface. Mucoadhesive drug delivery system may be designed to enable prolonged residence time of the dosage form at the site of application or absorption and facilitate an intimate contact of the dosage form with the underline absorption surface. Extending the residence time of a dosage form at a particular site and controlling the release of drug from the dosage form are useful especially for achieving controlled plasma level of the drug as well as improving bioavailability. Application of these dosage forms to mucosal surfaces may be of benefit to drug molecules not amenable to the oral route, such as those that undergo acid degradation or extensive first-pass metabolism. The present review describes mucoadhesion, mucoadhesive polymers and use of these polymers in designing different types of ...
Various minerals have been reported which are directly linked to our health and cancer developmen... more Various minerals have been reported which are directly linked to our health and cancer development in body. The immune system (immunoglobulin's, cell mediated immunity, phagocytosis complement, lysosomes, interferon, metabolic function, hormones, metabolic and respiratory alkalosis) is the natural mechanism which defends against cancer. Minerals like zinc, selenium, magnesium, vanadium, and germanium augment this natural mechanism. In this review various aspects of these mineral are discussed and their relation with cancer.
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Papers by Mankaran Singh