Purpose: Metastatic castration-resistant prostate cancer remains incurable regardless of recent t... more Purpose: Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Nonspecific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC 1553, with antiglycolytic activity. Experimental design: We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice was studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were car...
Obesity is among the most prevalent of health conditions in humans leading to a multitude of meta... more Obesity is among the most prevalent of health conditions in humans leading to a multitude of metabolic pathologies such as type 2 diabetes and hyperglycemia. However, there are many wild animals that have large seasonal cycles of fat accumulation and loss that do not result in the health consequences observed in obese humans. One example is the grizzly bear ( Ursus arctos horribilis ) that can have body fat content > 40% that is then used as the energy source for hibernation. Previous in vitro studies found that hibernation season adipocytes exhibit insulin resistance and increased lipolysis. Yet, other aspects of cellular metabolism were not addressed, leaving this in vitro model incomplete. Thus, the current studies were performed to determine if the cellular energetic phenotype—measured via metabolic flux—of hibernating bears was retained in cultured adipocytes and to what extent that was due to serum or intrinsic cellular factors. Extracellular acidification rate and oxygen consumption rate were used to calculate proton efflux rate and total ATP defined as both ATP from glycolysis and from mitochondrial respiration. Hibernation adipocytes treated with hibernation serum produced less ATP and exhibited lower maximal respiration and glycolysis rates than active season adipocytes. These effects were reversed with serum from the opposite season. Insulin had little influence on total ATP production and lipolysis in both hibernation and active serum-treated adipocytes. Together, these results suggest that the metabolic suppression occurring in hibernation adipocytes are downstream of insulin signaling and likely due to a combined reduction in mitochondria number and/or function and glycolytic processes. Future elucidation of the serum components and the cellular mechanisms that enable alterations in mitochondrial function could provide a novel avenue for the development of treatments for human metabolic diseases.
This report of an on-site evaluation of the Matlab Contraceptive Distribution Project considers t... more This report of an on-site evaluation of the Matlab Contraceptive Distribution Project considers the degree to which the project actually made contraceptives available the quality of data and analysis generated by the project and future uses of the data cost-effectiveness of the project and generalizations that can be drawn from it. The Contraceptive Distribution Project was started in 1975 to study the possible effectiveness of a family planning program in rural Bangladesh based solely on widespread availability of contraceptives. Funding from AID was terminated after the project was redesigned to allow program personnel to deliver basic health services as well as contraceptives. The demographic data base was found to be extensive and of high quality the system for contraceptive distribution to function well and the program to have been successful in reaching its target population. Clinical support services for contraceptive users and collection of family planning data were also fou...
Women, Work and Sociability in Early Modern London is Tim Reinke-Williams' first monograph, drawn... more Women, Work and Sociability in Early Modern London is Tim Reinke-Williams' first monograph, drawn from elements of his PhD thesis 'The negotiation and fashioning of female honour in early modern London'. (1) Crucially, it is also the first work dedicated solely to the exploration of how women from the 'middling sort' and labouring poor constructed identities as honest, hardworking individuals. Reinke-Williams argues that whilst scholarship on women in early modern England has grown substantially over the last 30 years, far more attention has been paid to negative attitudes, representations and behaviours. To put it in contemporary terms, historians of early modern women have been 'eagle-eyed in espying their faults, but dark-sighted owles, in perceiving their virtues'.(2) This is comprehensively illustrated in the author's overview of the historiography of female honour and reputation, mapping its course from Keith Thomas' initial exploration of the 'double standard' and the development of this argument by Laura Gowing, through to more recent studies by historians including Faramerz Dabhoiwala and Alexandra Shepard. Whilst it is now arguably a 'truism' within existing scholarship that sexual behaviour was only one way by which the reputations of women of early modern England were judged, there remains a vacancy for a 'holistic book-length study of early modern women of good repute' (p. 6).
Purpose: Metastatic castration-resistant prostate cancer remains incurable regardless of recent t... more Purpose: Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Nonspecific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC 1553, with antiglycolytic activity. Experimental design: We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice was studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were car...
Obesity is among the most prevalent of health conditions in humans leading to a multitude of meta... more Obesity is among the most prevalent of health conditions in humans leading to a multitude of metabolic pathologies such as type 2 diabetes and hyperglycemia. However, there are many wild animals that have large seasonal cycles of fat accumulation and loss that do not result in the health consequences observed in obese humans. One example is the grizzly bear ( Ursus arctos horribilis ) that can have body fat content > 40% that is then used as the energy source for hibernation. Previous in vitro studies found that hibernation season adipocytes exhibit insulin resistance and increased lipolysis. Yet, other aspects of cellular metabolism were not addressed, leaving this in vitro model incomplete. Thus, the current studies were performed to determine if the cellular energetic phenotype—measured via metabolic flux—of hibernating bears was retained in cultured adipocytes and to what extent that was due to serum or intrinsic cellular factors. Extracellular acidification rate and oxygen consumption rate were used to calculate proton efflux rate and total ATP defined as both ATP from glycolysis and from mitochondrial respiration. Hibernation adipocytes treated with hibernation serum produced less ATP and exhibited lower maximal respiration and glycolysis rates than active season adipocytes. These effects were reversed with serum from the opposite season. Insulin had little influence on total ATP production and lipolysis in both hibernation and active serum-treated adipocytes. Together, these results suggest that the metabolic suppression occurring in hibernation adipocytes are downstream of insulin signaling and likely due to a combined reduction in mitochondria number and/or function and glycolytic processes. Future elucidation of the serum components and the cellular mechanisms that enable alterations in mitochondrial function could provide a novel avenue for the development of treatments for human metabolic diseases.
This report of an on-site evaluation of the Matlab Contraceptive Distribution Project considers t... more This report of an on-site evaluation of the Matlab Contraceptive Distribution Project considers the degree to which the project actually made contraceptives available the quality of data and analysis generated by the project and future uses of the data cost-effectiveness of the project and generalizations that can be drawn from it. The Contraceptive Distribution Project was started in 1975 to study the possible effectiveness of a family planning program in rural Bangladesh based solely on widespread availability of contraceptives. Funding from AID was terminated after the project was redesigned to allow program personnel to deliver basic health services as well as contraceptives. The demographic data base was found to be extensive and of high quality the system for contraceptive distribution to function well and the program to have been successful in reaching its target population. Clinical support services for contraceptive users and collection of family planning data were also fou...
Women, Work and Sociability in Early Modern London is Tim Reinke-Williams' first monograph, drawn... more Women, Work and Sociability in Early Modern London is Tim Reinke-Williams' first monograph, drawn from elements of his PhD thesis 'The negotiation and fashioning of female honour in early modern London'. (1) Crucially, it is also the first work dedicated solely to the exploration of how women from the 'middling sort' and labouring poor constructed identities as honest, hardworking individuals. Reinke-Williams argues that whilst scholarship on women in early modern England has grown substantially over the last 30 years, far more attention has been paid to negative attitudes, representations and behaviours. To put it in contemporary terms, historians of early modern women have been 'eagle-eyed in espying their faults, but dark-sighted owles, in perceiving their virtues'.(2) This is comprehensively illustrated in the author's overview of the historiography of female honour and reputation, mapping its course from Keith Thomas' initial exploration of the 'double standard' and the development of this argument by Laura Gowing, through to more recent studies by historians including Faramerz Dabhoiwala and Alexandra Shepard. Whilst it is now arguably a 'truism' within existing scholarship that sexual behaviour was only one way by which the reputations of women of early modern England were judged, there remains a vacancy for a 'holistic book-length study of early modern women of good repute' (p. 6).
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Papers by Hannah Hogan