Bikul Das is a physician-researcher having 20 years of clinical experience in Internal Medicine including Oncology. His research is focussed on studying stem cell self-renewal in the microenvironment of hypoxia/oxidative stress. After completing PhD in University of Toronto, he started a non-profit lab, the KaviKrishna Lab in India'a Assam to promote his idea on stem cell altruism, and its role in cancer plus infectious diseases. He then completed a post-doctoral at Stanford University, and five years of faculty position at Forsyth Institute, Cambridge MA to further strengthen his Indian lab. Then, in 2018, he started a non-proift, Thoreau Lab for Global Health at M2D2 UMass Lowell, MA. Both the India and US labs now engaged in research on stem cell altruism, and its implication in understanding the pathogenesis of cancer and infectious diseases. He continues to practice medical oncology through his rural telemedicine clinic in India's Assam province, the KaviKrishna Telemedicine Care (KTC) that he started in the year 1994. His lab websites are: www.kavikrishnalab.org and www.thoreaulab.org
The maintenance of stemness of normal stem cell is a complex process, where transcription factors... more The maintenance of stemness of normal stem cell is a complex process, where transcription factors like Oct-4, Bmi-1, and signaling pathways such as Wnt/β-catenin play important roles. This molecular set of mechanisms not only expands the population (self-renewal) but also keeps stem cells in a state of “de-differentiation.” Thus, stemness and differentiation are mutually exclusive and tightly regulated, where the
Both theoretical and experimental evidence support the concept of a tumor stem cell (TSC) model -... more Both theoretical and experimental evidence support the concept of a tumor stem cell (TSC) model - a rare population of self-renewing stem cells among the heterogeneous mixture of tumor cells essential for solid tumor growth and progression. However, this growing evidence is not by itself convincing without an adequate molecular mechanism explaining how these TSCs maintain their stemness, since there is always a possibility that the so-called solid tumor TSCs may be a highly tumorigenic fraction of the heterogeneous mixture of tumor cells. The lack of knowledge of how TSCs maintain their state of stemness is therefore a major limitation that requires attention in order to improve our understanding on the stem cell model of tumor growth. An emerging and provocative concept in tumor biology is that a rare population of tumor stem cells exists among the heterogeneous population of cells within tumors. The TSC model suggests that proliferative potential and growth patterns of many human tumors may depend upon a small proportion of tumor stem cells that lead to repopulation following cytotoxic therapy. In this review, we will briefly discuss the basic concept of the TSC model and the emerging findings of the existence of the TSC fraction, even in established tumor cell lines.
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a global public health ... more Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a global public health threat and remains the leading cause of death among infectious diseases. The pathogen has developed strategies to survive inside and outside diverse host cells under wide range of unfavorable conditions, leading to persistence, and also undergo reactivation in the event of favorable conditions. Several sources of endogenous reactivation are proposed, including specific host cells that could harbor viable and dormant Mtb in the protective intracellular compartments. However, it is not clear how these host cells could survive the hypoxic/oxidative stress microenvironment prevalent in the post-drug treated granulomas. Recently Das et al. identified human CD271+ bone marrow mesenchymal stem cells (CD271+ BM-MSCs) as niche host cells that can maintain viable, non-replicating dormant Mtb. Most importantly, from patients who had successfully completed anti-tubercular therapy, viable Mtb could be isolated from CD271+ BM-MSCs, and not in other types of cells including macrophages. The follow-up study showed that Mtb could escape anti-tubercular drug therapy by hiding intracellular to CD271+ BM-MSCs serving as source for endogenous reactivation of TB. With these studies at the forefront, a novel model of granuloma reactivation could be proposed where CD271+ BM-MSCs harboring viable Mtb migrate to inflammatory granulomas for disease reactivation. Moreover, CD271+BM-MSCs also are able to resuscitate the viable but non-culturable (VBNC) Mtb inside the granuloma to reactivate the disease. Studies show that pulmonary tuberculosis (PTB) patients with culture negative sputum contain an occult population of VBNC Mtb in their sputum. CD271+ host-Mtb interaction studies suggest that these VBNC may be resuscitate back to culturable state by CD271+MSCs. Study of mechanism of Mtb survival and resuscitation inside MSCs is challenging and ongoing. Hypoxia may play an important role in the survival and persistence of Mtb inside the MSCs in TB patients post therapy as well in mice drug-induced dormancy model indicated by upregulation of HIF-1alpha. Latent TB has been challenging and difficult to study because of the dynamic capability of Mtb to adapt easily for over 200 years in vivo and in vitro. Despite all the ongoing efforts, so far, targeting dormant TB seems difficult. Although there are drugs which target cell wall synthesis, transcription, translation, and ATPase activity in actively dividing stage, their efficacy against dormant bacilli is unclear. Isoniazid treatment for 9 months is recommended for latent or dormant TB; however, non-adherence to such long regimen is a problem; moreover in light of current studies the efficacy of isoniazid against dormant bacilli is questionable. Studies on Mtb residing inside MSCs may shed light into new therapeutics to target non-replicating bacteria as well as VBNC Mtb and prevent endogenous reactivation of the disease.
Oral squamous cell carcinoma (OSCC) is a global health disease affecting developing countries, ma... more Oral squamous cell carcinoma (OSCC) is a global health disease affecting developing countries, mainly the South and South East Asian countries. This cancer type is mostly HPV-16 negative and exhibits aggressiveness and resistance to therapies. Our previous studies have shown an oral microbiota (Fusobacterium nucleatum a gram negative anaerobic bacillus) associated with tumour progression in oral squamous cell carcinoma (1). The enhanced degree of stemness involved may confer the CSCs to be highly aggressive, self-sufficient, transient and niche modulatory, the tumour stemness defense (TSD) phenotype (2). The TSD characteristics are expressed as a part of “stem cell niche defence mechanism” (2). The TSD phenotype in ABCG2+ CSCs are characterized by the activation of the MYC-HIF-2alpha stemness pathway (3), as well as altruistic defense mechanism (4). Here we further studied the role of F.N. in reprograming of oral CSCs to TSD phenotype. Methods: SCC-25 cell line containing EpCAM+/ABC...
Potential cell surface markers specifically enriching the leukemia stem cell (LSC) subfraction ba... more Potential cell surface markers specifically enriching the leukemia stem cell (LSC) subfraction based on stemness genes expression have not yet been identified. Previously, we reported ABCG2, a drug efflux pump, enriches a subpopulation of cells exhibiting a very high level of stemness genes expression in ES cells. These ABCG2+ ES cells exhibited high HIF-2α, which in cooperation with MYC-regulated Nanog and Sox-2. ABCG2+ cells demonstrated highly cytoprotective altruistic behavior by secreting high levels of glutathione. In the present study, we evaluated whether ABCG2+ subfraction of human LSCs exhibits high level of stemness genes and altruistic behavior. We isolated the ABCG2+ cell subfraction from cervical lymph node and blood of human T-ALL(n=5) and CML(n=7) patients exhibiting high levels of stemness genes in addition to MYC and HIF-2α. We investigated the altruistic stemness phenotype of the ABCG2+ cells by studying the molecular signature of MYC binding to HIF-2α. siRNA HIF-...
Supplemental Methods elaborate the details of each methodology/approaches being used in the manus... more Supplemental Methods elaborate the details of each methodology/approaches being used in the manuscript
Leukemia is hierarchically organized into two distinct population of cancer cells, cancer stem ce... more Leukemia is hierarchically organized into two distinct population of cancer cells, cancer stem cells (CSCs) and non-stem cancer cells (NSCC). Numerous studies suggest that CSCs may express embryonic stem (ES) cells related stemness genes including Nanog, Sox-2, and Oct-4. However, potential cell surface markers that could specifically enrich the leukemia stem cell (LSC) subfraction based on the expression of these stemness genes have not yet been identified. Previously, we reported that ABCG2, a drug efflux pump, could enrich a subpopulation of cells exhibiting very high level of Nanog, Sox-2, and Oct-4 in ES cells. Additionally, these ABCG2+ ES cells also exhibited high HIF-2α, a transcription factor, which in cooperation with MYC-regulated both Nanog and Sox-2. In addition to these features, ABCG2+ cells demonstrated highly cytoprotective altruistic behavior by secreting high levels of glutathione. In the present study, we evaluated whether ABCG2+ subfraction of human LSCs exhibit...
Background: Identification and characterization of novel molecular inhibitors that target key reg... more Background: Identification and characterization of novel molecular inhibitors that target key regulators of cancer stem cell (CSCs) self-renewal is promising in cancer therapeutics. MYC and p53, the two major cellular transcription factors, acts as key molecular regulators in stem cells and cancer stem cells self-renewal. While MYC enhances, p53 inhibits the self-renewal of stem cells. Thus, developing novel molecules that could potentially target either MYC and or p53 might potential therapeutic application. However, the search for small molecules that could target the self-renewal aspect of these two proteins has been elusive. Previously; we demonstrated that isoprenoid molecule squalene could enhance bone marrow hematopoietic and mesenchymal stem cells (MSCs) by modulating MYC. Importantly, we found that ursolic acid, an isoprenoid molecule found in Tulsi plant, inhibited HIF-1alpha, a transcription factor regulated by MYC and p53. Hence, having these prior experiences on isopren...
Background: Tumor hypoxia is a major contributing factor in cancer therapeutic failure. The micro... more Background: Tumor hypoxia is a major contributing factor in cancer therapeutic failure. The microenvironment of hypoxia/oxidative stress may reprogram cancer cells to highly tumorigenic, metastatic, angiogenic and stem cell-like state. We have characterized in vitro and in vivo models of hypoxia-induced cancer cell reprogramming to cancer stem cell (CSCs) like cells including an immunocompetent model of oral cancer. These CSCs exhibit ABCG2 cell surface marker. Numerous approaches including targeted therapy using oncolytic virus and bacteria have been attempted to target cancer cells in their hypoxic niche without major therapeutic success. Major therapeutic challenges include the inaccessibility of hypoxic niche by therapy-agents and the poor replication of viruses or bacteria intracellular to hypoxic cancer cells. Furthermore, the immune privileged microenvironment of tumor hypoxia could pose a challenge to viral/bacterial-induced immunity against the tumor. In this context, here ...
Oral squamous cell carcinoma (OSCC) is a global health challenge. The overall survival rate of th... more Oral squamous cell carcinoma (OSCC) is a global health challenge. The overall survival rate of this devastating disease has not significantly changed, and the biology of this type of cancer also remain largely unexplored. To enhance the understanding of this disease through global heath cancer research collaborative effort, we have set up an international collaboration between Forsyth Institute, Cambridge, and KaviKrishna laboratory, which is located in Kamrup district of Assam, having highest incidence of oral cancer in the world. Through this collaborative effort we intend to explore the role of hypoxia in oral cancer progression, metastasis and therapy resistance. Method: We used an oral squamous cell carcinoma cell line SSC25 for this purpose, and performed several experiments using a well-described in vitro assay of CSC self-renewal under hypoxia. Results: We identified a rare ABCG2+ expressing, highly tumorigenic cell population in SSC-25 having cancer stem cell (CSC) like cha...
1126 We had previously reported on the discovery of novel alpha-3 integrin binding peptides throu... more 1126 We had previously reported on the discovery of novel alpha-3 integrin binding peptides through screening “one- bead one-compound” combinatorial cyclic peptide libraries with live ovarian adenocarcinoma cell lines [1]. We have shown that these ligands can be used as effective probes to image ovarian tumor xenografts both optically [2] and with positron emission tomography. Based on the results obtained from the primary and secondary library screens, we have designed and synthesized four tertiary libraries that can be used to further optimize our lead compounds. These libraries include (a) main chain modification with three diversity points, (b) side chain modification with three diversity points, (c) main chain and N-terminal modifications, and (d) N-terminal extensions with two diversity points. By using this sequential iterative screening approach with a number of different combinatorial libraries, we can rapidly probe the conformational spaces surrounding the initial lead compound. We have also identified other novel peptides from random peptide library screening which have a common motif that bind to ovarian adenocarcinomas as well as transition cell tumors. Preliminary data shows that one of these identified peptides preferentially binds to beta-1 integrin. These peptides could potentially be used as carrier to delivery radionuclides or cytotoxic drugs to the target tumor. 1. Aina, O.H., et al., Identification of novel targeting peptides for human ovarian cancer cells using “one-bead one-compound” combinatorial libraries. Mol Cancer Ther, 2005. 4(5): p. 806-13. 2. Aina, O.H., et al., Near- Infrared optical imaging of ovarian cancer xenografts with novel alpha-3 integrin binding peptide “OA02”. Molecular Imaging, 2005.
Recently, we isolated a small fraction of migratory and hypoxia resistant side-population cells [... more Recently, we isolated a small fraction of migratory and hypoxia resistant side-population cells [SPm(hox)] from several solid tumors and demonstrated their in vivo localization in the hypoxic niche (1). These SPm (hox) cells are highly tumorigenic and express embryonic stem cell signature genes Oct 4 and Nanog, whereas non-migratory SP cells and non-SP cells are poorly tumorigenic and do not express Oct4/Nanog (1). The SPm (hox) fraction expressed a higher level of VEGFR1 (VEGF receptor, Flt1) compared to the non-SP fraction (2). Treatment with neutralizing anti-VEGF antibody rapidly converted SP to non-SP cells in vitro (3). Therefore, we hypothesized that VEGFR1 expressing SPm(hox) cells may initiate the formation of a \#8220;tumor initiation niche\#8221; in vivo. The \#8220;niche\#8221; may secrete a high level of VEGF to maintain the \#8220;stemness\#8221; state of the SPm(hox) cells. To investigate this possibility, SPm(hox) cells were isolated from SK-N-BE2 (neuroblastoma) and RH-4 (rhabdomyosarcoma) cell lines as described (1), mixed with matrigel and injected subcutaneously into Balb/c nude mice (50000 cells/plug; 8 mice). Ten days after the injection, matrigel plugs were studied for the microenvironmental changes including stromal cell infiltration, vessel cooption, angiogenesis, secretion of growth factors, and hypoxia/oxidative stress microenvironment as described (4). The SPm (hox) plug showed rapid proliferation of tumor cells, vessel cooption and marked infiltration of stromal cells within ten days of injection as compared to non-migratory SP cells (P Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3129.
The maintenance of stemness of normal stem cell is a complex process, where transcription factors... more The maintenance of stemness of normal stem cell is a complex process, where transcription factors like Oct-4, Bmi-1, and signaling pathways such as Wnt/β-catenin play important roles. This molecular set of mechanisms not only expands the population (self-renewal) but also keeps stem cells in a state of “de-differentiation.” Thus, stemness and differentiation are mutually exclusive and tightly regulated, where the
Both theoretical and experimental evidence support the concept of a tumor stem cell (TSC) model -... more Both theoretical and experimental evidence support the concept of a tumor stem cell (TSC) model - a rare population of self-renewing stem cells among the heterogeneous mixture of tumor cells essential for solid tumor growth and progression. However, this growing evidence is not by itself convincing without an adequate molecular mechanism explaining how these TSCs maintain their stemness, since there is always a possibility that the so-called solid tumor TSCs may be a highly tumorigenic fraction of the heterogeneous mixture of tumor cells. The lack of knowledge of how TSCs maintain their state of stemness is therefore a major limitation that requires attention in order to improve our understanding on the stem cell model of tumor growth. An emerging and provocative concept in tumor biology is that a rare population of tumor stem cells exists among the heterogeneous population of cells within tumors. The TSC model suggests that proliferative potential and growth patterns of many human tumors may depend upon a small proportion of tumor stem cells that lead to repopulation following cytotoxic therapy. In this review, we will briefly discuss the basic concept of the TSC model and the emerging findings of the existence of the TSC fraction, even in established tumor cell lines.
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a global public health ... more Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a global public health threat and remains the leading cause of death among infectious diseases. The pathogen has developed strategies to survive inside and outside diverse host cells under wide range of unfavorable conditions, leading to persistence, and also undergo reactivation in the event of favorable conditions. Several sources of endogenous reactivation are proposed, including specific host cells that could harbor viable and dormant Mtb in the protective intracellular compartments. However, it is not clear how these host cells could survive the hypoxic/oxidative stress microenvironment prevalent in the post-drug treated granulomas. Recently Das et al. identified human CD271+ bone marrow mesenchymal stem cells (CD271+ BM-MSCs) as niche host cells that can maintain viable, non-replicating dormant Mtb. Most importantly, from patients who had successfully completed anti-tubercular therapy, viable Mtb could be isolated from CD271+ BM-MSCs, and not in other types of cells including macrophages. The follow-up study showed that Mtb could escape anti-tubercular drug therapy by hiding intracellular to CD271+ BM-MSCs serving as source for endogenous reactivation of TB. With these studies at the forefront, a novel model of granuloma reactivation could be proposed where CD271+ BM-MSCs harboring viable Mtb migrate to inflammatory granulomas for disease reactivation. Moreover, CD271+BM-MSCs also are able to resuscitate the viable but non-culturable (VBNC) Mtb inside the granuloma to reactivate the disease. Studies show that pulmonary tuberculosis (PTB) patients with culture negative sputum contain an occult population of VBNC Mtb in their sputum. CD271+ host-Mtb interaction studies suggest that these VBNC may be resuscitate back to culturable state by CD271+MSCs. Study of mechanism of Mtb survival and resuscitation inside MSCs is challenging and ongoing. Hypoxia may play an important role in the survival and persistence of Mtb inside the MSCs in TB patients post therapy as well in mice drug-induced dormancy model indicated by upregulation of HIF-1alpha. Latent TB has been challenging and difficult to study because of the dynamic capability of Mtb to adapt easily for over 200 years in vivo and in vitro. Despite all the ongoing efforts, so far, targeting dormant TB seems difficult. Although there are drugs which target cell wall synthesis, transcription, translation, and ATPase activity in actively dividing stage, their efficacy against dormant bacilli is unclear. Isoniazid treatment for 9 months is recommended for latent or dormant TB; however, non-adherence to such long regimen is a problem; moreover in light of current studies the efficacy of isoniazid against dormant bacilli is questionable. Studies on Mtb residing inside MSCs may shed light into new therapeutics to target non-replicating bacteria as well as VBNC Mtb and prevent endogenous reactivation of the disease.
Oral squamous cell carcinoma (OSCC) is a global health disease affecting developing countries, ma... more Oral squamous cell carcinoma (OSCC) is a global health disease affecting developing countries, mainly the South and South East Asian countries. This cancer type is mostly HPV-16 negative and exhibits aggressiveness and resistance to therapies. Our previous studies have shown an oral microbiota (Fusobacterium nucleatum a gram negative anaerobic bacillus) associated with tumour progression in oral squamous cell carcinoma (1). The enhanced degree of stemness involved may confer the CSCs to be highly aggressive, self-sufficient, transient and niche modulatory, the tumour stemness defense (TSD) phenotype (2). The TSD characteristics are expressed as a part of “stem cell niche defence mechanism” (2). The TSD phenotype in ABCG2+ CSCs are characterized by the activation of the MYC-HIF-2alpha stemness pathway (3), as well as altruistic defense mechanism (4). Here we further studied the role of F.N. in reprograming of oral CSCs to TSD phenotype. Methods: SCC-25 cell line containing EpCAM+/ABC...
Potential cell surface markers specifically enriching the leukemia stem cell (LSC) subfraction ba... more Potential cell surface markers specifically enriching the leukemia stem cell (LSC) subfraction based on stemness genes expression have not yet been identified. Previously, we reported ABCG2, a drug efflux pump, enriches a subpopulation of cells exhibiting a very high level of stemness genes expression in ES cells. These ABCG2+ ES cells exhibited high HIF-2α, which in cooperation with MYC-regulated Nanog and Sox-2. ABCG2+ cells demonstrated highly cytoprotective altruistic behavior by secreting high levels of glutathione. In the present study, we evaluated whether ABCG2+ subfraction of human LSCs exhibits high level of stemness genes and altruistic behavior. We isolated the ABCG2+ cell subfraction from cervical lymph node and blood of human T-ALL(n=5) and CML(n=7) patients exhibiting high levels of stemness genes in addition to MYC and HIF-2α. We investigated the altruistic stemness phenotype of the ABCG2+ cells by studying the molecular signature of MYC binding to HIF-2α. siRNA HIF-...
Supplemental Methods elaborate the details of each methodology/approaches being used in the manus... more Supplemental Methods elaborate the details of each methodology/approaches being used in the manuscript
Leukemia is hierarchically organized into two distinct population of cancer cells, cancer stem ce... more Leukemia is hierarchically organized into two distinct population of cancer cells, cancer stem cells (CSCs) and non-stem cancer cells (NSCC). Numerous studies suggest that CSCs may express embryonic stem (ES) cells related stemness genes including Nanog, Sox-2, and Oct-4. However, potential cell surface markers that could specifically enrich the leukemia stem cell (LSC) subfraction based on the expression of these stemness genes have not yet been identified. Previously, we reported that ABCG2, a drug efflux pump, could enrich a subpopulation of cells exhibiting very high level of Nanog, Sox-2, and Oct-4 in ES cells. Additionally, these ABCG2+ ES cells also exhibited high HIF-2α, a transcription factor, which in cooperation with MYC-regulated both Nanog and Sox-2. In addition to these features, ABCG2+ cells demonstrated highly cytoprotective altruistic behavior by secreting high levels of glutathione. In the present study, we evaluated whether ABCG2+ subfraction of human LSCs exhibit...
Background: Identification and characterization of novel molecular inhibitors that target key reg... more Background: Identification and characterization of novel molecular inhibitors that target key regulators of cancer stem cell (CSCs) self-renewal is promising in cancer therapeutics. MYC and p53, the two major cellular transcription factors, acts as key molecular regulators in stem cells and cancer stem cells self-renewal. While MYC enhances, p53 inhibits the self-renewal of stem cells. Thus, developing novel molecules that could potentially target either MYC and or p53 might potential therapeutic application. However, the search for small molecules that could target the self-renewal aspect of these two proteins has been elusive. Previously; we demonstrated that isoprenoid molecule squalene could enhance bone marrow hematopoietic and mesenchymal stem cells (MSCs) by modulating MYC. Importantly, we found that ursolic acid, an isoprenoid molecule found in Tulsi plant, inhibited HIF-1alpha, a transcription factor regulated by MYC and p53. Hence, having these prior experiences on isopren...
Background: Tumor hypoxia is a major contributing factor in cancer therapeutic failure. The micro... more Background: Tumor hypoxia is a major contributing factor in cancer therapeutic failure. The microenvironment of hypoxia/oxidative stress may reprogram cancer cells to highly tumorigenic, metastatic, angiogenic and stem cell-like state. We have characterized in vitro and in vivo models of hypoxia-induced cancer cell reprogramming to cancer stem cell (CSCs) like cells including an immunocompetent model of oral cancer. These CSCs exhibit ABCG2 cell surface marker. Numerous approaches including targeted therapy using oncolytic virus and bacteria have been attempted to target cancer cells in their hypoxic niche without major therapeutic success. Major therapeutic challenges include the inaccessibility of hypoxic niche by therapy-agents and the poor replication of viruses or bacteria intracellular to hypoxic cancer cells. Furthermore, the immune privileged microenvironment of tumor hypoxia could pose a challenge to viral/bacterial-induced immunity against the tumor. In this context, here ...
Oral squamous cell carcinoma (OSCC) is a global health challenge. The overall survival rate of th... more Oral squamous cell carcinoma (OSCC) is a global health challenge. The overall survival rate of this devastating disease has not significantly changed, and the biology of this type of cancer also remain largely unexplored. To enhance the understanding of this disease through global heath cancer research collaborative effort, we have set up an international collaboration between Forsyth Institute, Cambridge, and KaviKrishna laboratory, which is located in Kamrup district of Assam, having highest incidence of oral cancer in the world. Through this collaborative effort we intend to explore the role of hypoxia in oral cancer progression, metastasis and therapy resistance. Method: We used an oral squamous cell carcinoma cell line SSC25 for this purpose, and performed several experiments using a well-described in vitro assay of CSC self-renewal under hypoxia. Results: We identified a rare ABCG2+ expressing, highly tumorigenic cell population in SSC-25 having cancer stem cell (CSC) like cha...
1126 We had previously reported on the discovery of novel alpha-3 integrin binding peptides throu... more 1126 We had previously reported on the discovery of novel alpha-3 integrin binding peptides through screening “one- bead one-compound” combinatorial cyclic peptide libraries with live ovarian adenocarcinoma cell lines [1]. We have shown that these ligands can be used as effective probes to image ovarian tumor xenografts both optically [2] and with positron emission tomography. Based on the results obtained from the primary and secondary library screens, we have designed and synthesized four tertiary libraries that can be used to further optimize our lead compounds. These libraries include (a) main chain modification with three diversity points, (b) side chain modification with three diversity points, (c) main chain and N-terminal modifications, and (d) N-terminal extensions with two diversity points. By using this sequential iterative screening approach with a number of different combinatorial libraries, we can rapidly probe the conformational spaces surrounding the initial lead compound. We have also identified other novel peptides from random peptide library screening which have a common motif that bind to ovarian adenocarcinomas as well as transition cell tumors. Preliminary data shows that one of these identified peptides preferentially binds to beta-1 integrin. These peptides could potentially be used as carrier to delivery radionuclides or cytotoxic drugs to the target tumor. 1. Aina, O.H., et al., Identification of novel targeting peptides for human ovarian cancer cells using “one-bead one-compound” combinatorial libraries. Mol Cancer Ther, 2005. 4(5): p. 806-13. 2. Aina, O.H., et al., Near- Infrared optical imaging of ovarian cancer xenografts with novel alpha-3 integrin binding peptide “OA02”. Molecular Imaging, 2005.
Recently, we isolated a small fraction of migratory and hypoxia resistant side-population cells [... more Recently, we isolated a small fraction of migratory and hypoxia resistant side-population cells [SPm(hox)] from several solid tumors and demonstrated their in vivo localization in the hypoxic niche (1). These SPm (hox) cells are highly tumorigenic and express embryonic stem cell signature genes Oct 4 and Nanog, whereas non-migratory SP cells and non-SP cells are poorly tumorigenic and do not express Oct4/Nanog (1). The SPm (hox) fraction expressed a higher level of VEGFR1 (VEGF receptor, Flt1) compared to the non-SP fraction (2). Treatment with neutralizing anti-VEGF antibody rapidly converted SP to non-SP cells in vitro (3). Therefore, we hypothesized that VEGFR1 expressing SPm(hox) cells may initiate the formation of a \#8220;tumor initiation niche\#8221; in vivo. The \#8220;niche\#8221; may secrete a high level of VEGF to maintain the \#8220;stemness\#8221; state of the SPm(hox) cells. To investigate this possibility, SPm(hox) cells were isolated from SK-N-BE2 (neuroblastoma) and RH-4 (rhabdomyosarcoma) cell lines as described (1), mixed with matrigel and injected subcutaneously into Balb/c nude mice (50000 cells/plug; 8 mice). Ten days after the injection, matrigel plugs were studied for the microenvironmental changes including stromal cell infiltration, vessel cooption, angiogenesis, secretion of growth factors, and hypoxia/oxidative stress microenvironment as described (4). The SPm (hox) plug showed rapid proliferation of tumor cells, vessel cooption and marked infiltration of stromal cells within ten days of injection as compared to non-migratory SP cells (P Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3129.
KaviKrishna Laboratory: recovering the spirit of Vedic Jiva Upakara Tantra, 2019
Vedic Jiva Upakara Tantra is a cikitsha (medical) tantra (system of knowledge) of ancient Kamarup... more Vedic Jiva Upakara Tantra is a cikitsha (medical) tantra (system of knowledge) of ancient Kamarupa (present day Assam). The Tantra is a part of the ancient Vedic system of Pancha kosha (five bodily sheaths) based healing methods, but incorporate a sixth kosha, the Avatar Kosha. The Avatar kosha has potent healing power, but it is transient, and only activated during stress. In this book, the oral tradition of the Tantra, the metaphysics, plus how this tantra is contributing to the biomedical as well as Medical Humanities research at KaviKrishna Lab/IIT-Guwahati has been described. The book is the results of 25 years of ethnography study, plus clinical/research experience at KaviKrishna telemedicine center located in Sualkuchi, Assam, India.
This book was published in the year 2000, and it describes the evolutionary presence of antioxida... more This book was published in the year 2000, and it describes the evolutionary presence of antioxidant squalene in human skin. The book proposed the need for research on the evolutionary and altruistic aspects of nutrient research. The book also proposed an idea of the ancestral stem cell niche defense and the potential role of endogenous antioxidants such as squalene and glutathione in this niche defense. On page 12, the idea of "Avatar Kosha" the key metaphysic of Vedic Jiva Upakara Tantra (Vedic Altruism), is mentioned.
Assamese researcher stands tall internationally-lays the runway by Nidarshana Saikia Das While me... more Assamese researcher stands tall internationally-lays the runway by Nidarshana Saikia Das While medical research in Assam is still grappling through its nascent stage, Dr. Bikul Das, now a research scientist in the world famous Stanford University, California, U.S.A., brings home a beacon of hope in the form of a $100,000 grant that the Gates Foundation has awarded him for his research endeavor. He has also received so far more than half-a-million dollar grant from government and private foundations of North America to conduct his research on cancer and stem cells. He shares his experience and etches the trajectory for young research enthusiasts in Assam to follow suit.
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