Dissertations / Theses on the topic 'Prostratine'

L’infection par HIV-1 représente un des problèmes de santé publique majeurs de notre société actuelle. Le traitement HAART (Highly Active AntiRetroviral Therapy) inhibe le cycle réplicatif viral mais ne permet pas l’éradication du HIV-1. La principale cause de cet échec thérapeutique est la persistance de réservoirs cellulaires infectés de manière latente par HIV-1, qui, lors de l’arrêt du traitement HAART, sont à l’origine d’un rebond de la charge plasmatique virale. Le défi actuel est donc de découvrir de nouvelles méthodes d’élimination des cellules réservoirs. Une des stratégies envisagées est de forcer l’expression virale dans les cellules infectées de manière latente afin d’entraîner leur destruction suite à leur détection par le système immunitaire ou suite aux effets cytopathiques viraux. Parallèlement, le traitement HAART serait maintenu afin de limiter la propagation des virions néo-synthétisés. Plusieurs éléments sont impliqués dans la répression transcriptionnelle associée à la latence post-intégrationnelle du virus HIV-1 :la nature du site d’intégration ;l’absence de facteurs cellulaires inductibles tels que NF-κB ;la structure chromatinienne du provirus et les modifications post-traductionnelles des histones ;l’absence de niveaux suffisants de la protéine trans-activatrice Tat. De plus, notre laboratoire a précédemment mis en évidence un lien entre deux de ces éléments, en démontrant, dans une lignée modèle de latence post-intégrationnelle, que la cytokine pro-inflammatoire TNFα, un activateur de la voie de signalisation NF-κB, permet une réactivation synergique de l’expression virale combinée à l’inhibiteur d’histone-désacétylases (HDACI) TSA. Cependant, l’utilisation thérapeutique du TNFα et de la TSA est inenvisageable en raison de leurs toxicités.

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Doctorat en Sciences
info:eu-repo/semantics/nonPublished

Treatment options for patients with advanced prostate cancer (PC) still remain limited and rarely curative. The prostatic acid phosphatase (PAP) is prostate specific protein over-expressed in more than 90% of prostate tumours. Although an FDA-approved vaccine for the treatment of advanced prostate disease, PROVENGE® (sipuleucel-T), has been shown to prolong survival, the precise sequence of the PAP protein responsible for the outcome remains unknown. As the PAP antigen is one of the very few prostate-specific antigens for which there is a rodent equivalent with high homology, pre-clinical studies using PAP have the potential to be directly relevant to the clinical setting. The current study identified HLA-A2 and HLA-DR1 PAP-derived peptides using the transgenic HHDII/DR1 and C57Bl/6 mice. The PAP-114-128 (15-mer) peptide was shown to elicit CD4+ and CD8+ T-cell-specific responses in C57Bl/6 mice. Furthermore, when immunised in a DNA vector format (ImmunoBody), PAP-114-128 was able to prevent and reduce the growth of TRAMP C1 prostate cancer cell-derived tumours in both prophylactic and therapeutic settings. This anti-tumour effect was associated with an enhanced infiltration of CD8+ tumour-infiltrating lymphocytes (TILs) and the generation of high avidity T cells secreting elevated levels of IFNγ. Importantly, PAP-114-128 specific IFNγ response was also seen in PBMC isolated from PC patients. Also, immunisation of C57Bl/6 and HHDII/DRI mice with the analogue peptide epitope (obtained by altering the second amino acid of PAP-114-128) showed significantly enhanced IFNγ response compared to PAP-114-128 epitope. Collectively, PAP-114-128 appears to be a highly relevant peptide on which to base vaccines for the treatment of advanced PC.

(Uncorrected OCR) Abstract of thesis entitled Telomerase activation and telomeric repeats alteration in sex hormone-induced prostatic carcinogenesis in the Noble rat submitted by Chan Ching for the Degree of Master of Philosophy at the University of Hong Kong In November, 1998 Despite its distinction as the most frequently diagnosed cancer and the�second leading cause of cancer deaths in men, little is known about the causes and mechanisms of prostatic carcinogenesis. The animal model, based on the existing sex hormone-induced prostate carcinogenesis in the Noble rat, by substantially increasing the dosage of testosterone while keeping the level of estrogen unchanged has been reported. With this modified protocol, we have successfully induced high incidence of prostate carcinoma in Noble rats. The earliest time of development of dysplasia was two months, carcinoma in situ at 4 months and fully developed carcinoma at six months. The tumor incidence was 92% after 12 months hormonal implantation. This animal model is very useful in the investigation of prostate cancer as its multi -step nature mimics the human situation and its high incidence in relative short time. Telomerase activation is a characteristic of immortalized tumor cells and is thought to contribute to the mechanism by which these cells abort the normal process of senescence. Telomerase activity has been detected in various human cancers and there are reports showing that telomeric repeat fragment (TRF) length may be correlated to the staging of tumors. These findings suggested that telomerase activation and TRF length alteration might be useful in prognosis of different cancers. Study of prostate cancer on animal model can compensate for the difficulties in human cancer research, as stage-by-stage investigations are available. In this study, we proposed that telomerase would be activated in sex hormone-induced prostatic carcinogenesis and TRF length alterations might be correlated to the different stages of prostatic carcinogenesis. We have examined the telomerase activation as well as telomeric repeat fragment content alteration in the hormonal induced prostatic carcinogenesis in Noble rat. Telomerase activation is common in prostate carcinoma and also can be detected in 12% of non-malignant tissues. For the non-prostatic tissues tested, all the testis tissues (n=5) were strongly positive for telomerase activity and only one liver tissue (n=5) showed weak. telomerase activity. The high frequency of telomerase activation in prostatic carcinoma specimens suggested that it might be a useful malignancy marker for prognosis evaluation in prostatic carcinogenesis. There were alterations of TRF content in dorsal lateral prostate. The ventral prostate tissues have the similar results as the dorsal lateral prostate. It seems that the TRF content in normal tissues is less than that of hyperplasia, dysplasia and carcinoma tissues. However, no obvious relationships between the TRF content and clinicopathological properties of prostatic carcinogenesis were observed. Also, there was no significant relation between the telomerase activation and TRF content in this study. Hence, the TRF content appear to have no significant correlation with prostatic carcinogenesis.
abstract
toc
Anatomy
Master
Master of Philosophy

In Sweden, close to 10 000 men are annually diagnosed with prostate cancer (PCa) and approximately 2400 men die of their disease each year. Today there is no reliable marker that can separate patients who will have an aggressive type of disease that requires treatment, from patients who will have a more indolent clinical course and can be left untreated. This further leads to the current problem of over treatment of men with PCa. Hence, there is an urgent need for reliable prognostic markers that can be used at time of diagnosis. With the discovery of recurrent gene rearrangements in PCa, most commonly ERG rearrangements, hope came that this aberration could play a role in diagnosis and/or prognosis of the disease. The aim of this thesis was to investigate the clinical implication of ERG rearrangements in the management of PCa. The work in this thesis supports the findings from previous studies, suggesting that the ERG rearrangement is a sign of a more aggressive type of cancer. The major findings are that in multifocal PCa, the ERG rearranged cancer foci are more prone to metastatic dissemination compared to foci without the ERG rearrangement and that patients harboring the ERG rearrangement have a faster disease progression leading up to earlier start of hormonal treatment. Furthermore, the results add an additional level of complexity in a subset of PCa tumors that harbor multiple gene rearrangements on the cellular level. The result also show that the newly available ERG antibody is highly predictive of ERG rearrangement and is appropriate to use when faced with limitations in tissue amounts. The findings in this thesis indicate that the ERG rearrangement has a potential role in the clinical management of PCa but further studies arerequired.

Prostrate juniper heath (H15 Calluna vulgaris-Juniperus communis subspecies nana heath) is of considerable conservation importance. Its infrequent distribution in northwest Scotland is often attributed to historical burning. The intraspecific taxonomy of Juniperus communis L (Cupressaceae) is unclear. This thesis seeks to understand the history and current status of the community, and to clarify the taxonomy of juniper in Scotland. The impact of current levels of land use on extant HI5 was found to be low. A study of the environmental conditions associated with HI5 revealed that the community was absent from large areas of north-west Scotland with suitable conditions. Other communities with only infrequent juniper exist in many such areas. Sites with environmental conditions suitable for HI5 were investigated using palaeoecological methods. Fire had occurred in both HI5and non-H15 sites, but there was a prolonged recent absence in HI5. A study of annual growth rings showed juniper in HI5 to be twice as old as in other communities, emphasising the lack of recent disturbance. Evidence of greater past juniper cover was not found on non-H15 sites. It is argued that the history of prostrate juniper heath is more dynamic and complex than previously believed. Comparative morphological, genetic marker, and reciprocal transplant studies of juniper populations showed that Juniperus communis ssp. nana is characterised by genotypic prostrateness, imbricate leaf arrangement, and abrupt leaf tips. It is argued that the conservation importance of HI5 and juniper are increased by the findings of this study. Implications for conservation practice, and future research, are considered.

Thesis (Ph.D.)--Tufts University, 2001.
Adviser: Shuk-mei Ho. Submitted to the Dept. of Biology. Includes bibliographical references (leaves 178-196). Access restricted to members of the Tufts University community. Also available via the World Wide Web;

Prostate cancer is the most commonly diagnosed malignancy in males in the United States and its, progression depends on active androgen receptor (AR) signalling. Androgen deprivation therapy provides palliation but not cure, and the disease progresses to castration-resistant prostate cancer (CRPC). The taxanes represent the most effective class of anti-tumour agents that improve survival in CRPC patients. However, their benefits are transient and nearly all patients eventually progress. Understanding the molecular basis of taxane activity in prostate cancer is imperative for establishing successful treatment of this disease. The work in this study shows that AR associates with microtubules and that taxanes impair the ligand-induced nuclear accumulation of AR. Furthermore, co-immunoprecipitation assays and confocal microscopy revealed that AR trafficking towards the nucleus occurs along microtubules with the aid of the dynein motor protein. These results have been extended to two clinically relevant, ligand- independent AR splice variants, ARv567 and AR-V7. Live cell imaging experiments showed that ARv567 is dependent on microtubules in the same way as the full-length receptor, as pretreatment with microtubule-targeting drugs abrogated nuclear accumulation of both. However, this does not apply to the AR-V7 variant, which is not under microtubule control and remains insensitive to taxane treatment. Furthermore, the results show that ARv567, but not AR- V7, associates with microtubules as evidenced by microtubule co- sedimentation assays and requires dyne in for its nuclear translocation. In addition, deletion mutants of the AR show that the DNA binding domain and hinge region of the receptor are important for microtubule binding. Taken together, these data suggest that inhibition of AR nuclear accumulation underlies, in part, the activity of taxanes in CRPC revealing a new mechanism of action for this class of drugs and that the presence of AR splice variants may determine the clinical efficacy of taxane chemotherapy.

The majority of prostate cancer cases are shown to be androgen-dependant for growth as the blocking of androgen production has shown to reduce the size of prostate metastasis. The biosynthesis of the androgens is catalysed by the cytochrome P450 enzyme 17a-hydroxylase/17,20-lyase (P45017a) by converting the C21 steroids (pregnenolone and progesterone) to the androgens (dehydroepiandrosterone and androstenedione, respectively). Inhibition of P45017a would therefore bring about a decrease in the level of androgen production and furthermore prevent an increase in the stimulation of androgen-dependent prostate cancer cells. The current study was concerned with designing and synthesising compounds which were able to donate a lone pair of electrons to the Fe atom of the haem group with in the active site of the enzyme P45017a. As well as this, we were also interested in being able to mimic the C(3) of the natural substrate by varying the R group. In doing so, we were able to observe the impact of the interactions which take place within the active site. The compounds synthesised are based on the benzyl imidazole and the imidazolphenyl ethanonebackbone, where a small number of the synthesised products are phenyl alkyl imidazole based compounds, in order to consider physiochemical factors like hydrophobicity. Overall, the results of the study showed that the benzyl imidazole-based compounds were comparable to that of the standard ketoconazole (KTZ) in their inhibitory activity against 17,20-lyase and 17a-OHase (KTZ; %inhibition = 75% against 17,20-lyase: %inhibition = 64% against 17a-OHase). The nitro substituted derivatives (270-272) were shown to have improved inhibitory activity when compared to KTZ against 17a-OHase. With respect to the imidazol-phenyl ethananes, all with the exception of the 3-bromo substituted derivative ~88) were shown to possess either equipotent inhibitory activity to that of KTZ (%inhibition = 80% against 17a-OHase: %inhibiton = 82% against 17,20-lyase) or substantially lower activity. Compound 288 was found to possess greater inhibitory activity against the 17a-OHase component (288 %inhibition = 84%). Deliberation of structure-activity relationships determined no obvious correlation between the substitution pattern of the benzyl ring and the inhibitory activity against 17,20-lyase in the benzyl imidazole-based compounds. However, in the activity against 17a-OHase, a general trend towards the para substitution of the benzyl ring was shown to have an impact on the inhibition of the enzyme. In the imidazol-phenyl ethananes, consideration of the inhibitory activity of the halogen derivatives shows that there is an increase in potency with decreasing electronegativity of substituent group. In the inhibitory activity against 17a-OHase, some compounds show a correlation between decreasing electron-withdrawing ability and an increase in percentage inhibition. This would therefore appear to suggest that an ·interaction exists between the substituent and complementary group(s) at the active site of the enzyme - this interaction appears to be weaker within derivatives which possess substituents of high electronegativity. The substitution of the phenyl ring was too shown to influence the inhibitory activity of the compounds, which was rationalised by use of the SHC approach. This was proposed as results clearly indicate that the meta-substituted compounds were found to possess greater inhibitory activity in comparison to the para-substituted compounds.

PSbMV in field pea has resulted in substantial yield and seed quality losses world-wide and has recently been reported in North Dakota. Traditional management of this virus includes preventative measures such as removal of alternate hosts, planting virus free seed and the use of cultivar resistance. The objectives of this research were to screen field pea cultivars commonly grown in North Dakota for a response to North Dakota PSbMV isolate ND14-1 and ascertain the effect on plant symptoms, seed size and weight, the number of pods and seeds and seed transmission. Two cultivars were identified as highly resistant and one as partially resistant. The results from this study were combined into a risk assessment. Cultivars were categorized based on inherent risk of PSbMV infection, transmission and reduction in total seed weight. Common bacterial blight (CBB) in dry bean is capable of causing substantial yield losses and has been reported in up to 75% of fields in the Northarvest region in the last five years. Current management practices include the use of planting clean seed, crop rotation, partial host resistance and the application of cupric bactericides, although inconsistent for the management of CBB. Growers in this Northarvest region have recently shifted to growing upright (Type II) dry beans rather than prostrate (Type III) dry beans for ease of harvest. The objectives of this research were to evaluate copper products, surface sanitizers and growth promoters for the management of CBB and to discern if Type II dry beans experienced greater yield losses under CBB disease pressure than Type III dry beans. Numerous products were identified that significantly reduced CBB disease severity and spread; however, no significant yield benefit was observed. Across a wide range of disease severity (0-46%), no significant yield losses were observed between high and low disease severity any of the cultivars screened.

L’obstacle majeur à l’éradication du VIH est l’existence de réservoirs cellulaires du VIH, qui échappent au traitement et à la réponse immunitaire de l’hôte. Ce réservoir s’établit très tôt dans l’infection, menant typiquement à la destruction d’un grand nombre de lymphocytes T CD4+. Cependant, une faible proportion de ces cellules retourne à l’état quiescent en ayant intégré le génome viral. La taille et l’évolution du réservoir chez l’adulte ont été bien élucidées. Cependant, on en sait moins sur la taille et la distribution du réservoir du VIH, et sur l’impact de l’initiation précoce de la thérapie antirétrovirale combinée (TARc) sur ces dernières dans la population infantile. Cet essai s’inscrit dans le cadre de l’étude prospective multicentrique EPIC4 (Early Pediatric Initiation, Canada Child Cure Cohort Study), qui a recruté 221 enfants infectés par la voie verticale dans neuf centres pédiatriques canadiens. Nous soumettons l’hypothèse que l'initiation très précoce de la TARc chez l’enfant infecté par le VIH permettrait de réduire le réservoir à ses plus bas niveaux, menant à un meilleur contrôle de la réplication virale suite à une éventuelle interruption de traitement. Nous avons obtenu des corrélations positives entre la taille du réservoir viral lymphocytaire sanguin du VIH-1 et l'âge de l’initiation de la TARc et l'âge à la suppression virale soutenue (SVS). Les niveaux des réservoirs sont négativement corrélés à la proportion de la vie sous TARc efficace et à la proportion de la vie sous SVS et au compte de lymphocytes T CD4+. Nous avons montré également qu’un traitement initié précocement dans les premiers six mois de vie serait un facteur de prédictions d’une suppression virale plus rapide et plus soutenue. Nos résultats confirment que l’initiation précoce de la TARc et le maintien à long terme de la suppression virale stable sont des facteurs clés conduisant à une taille limitée du réservoir viral. Par ailleurs, nous démontrons pour la première fois que la taille du réservoir inductible du VIH-1 mesurée dans les lymphocytes T CD4+ du sang périphérique après stimulation avec un analogue de prostratine corrèle significativement avec celle mesurée en ADN proviral. Ainsi, nous avons validé une nouvelle technique de mesure de réservoir inductible qui est rapide et moins coûteuse et surtout requiert un faible volume de sang donc semble très prometteuse pour des études sur le VIH-1 pédiatrique.
The major barrier to eradicating HIV is the existence of cellular reservoirs of HIV, which escape the treatment and immune response of the host. This reservoir is established very early in the infection, typically leading to the destruction of a large number of CD4+ T cells. However, a small proportion of these cells return to quiescent state after integrating the viral genome. The size and evolution of the reservoir in adults have been well understood. However, we know less about the size and distribution of the HIV reservoir, and the impact of early initiation of combination antiretroviral therapy (cART) on it in the infant population. Our study is a part of the Early Pediatric Initiation Canada, Child Cure Cohort (EPIC4); a prospective, multicenter study, which enrolled 221 vertically HIV-1 infected children in nine Canadian pediatric centers. We hypothesize that very early initiation of cART in HIV-infected children would reduce the reservoir to its lowest levels, leading to better control of viral replication following a possible interruption of treatment. A strong positive correlation was observed between reservoir size in peripheral blood and both the age at initiation of cART and the age at which sustained viral suppression (SVS) was achieved. We found a strong negative correlation between the size of the viral reservoir and the proportion of life spent on effective cART or the proportion of life with SVS and CD4+ T lymphocytes count. This study shows that starting cART within 6 months from birth is a predictor of faster and more sustained virological suppression in infants. Our findings suggest that early cART initiation in infants and long-term viral suppression are key factors leading to limited viral reservoir size. Furthermore, we established for the first time that the size of the inducible HIV-1 reservoir in peripheral blood CD4+ T lymphocytes of children, quantified by the prostratin analogue stimulation test, correlates with the size obtained using proviral DNA measurement. Thus, we have validated a new inducible reservoir measurement technique that is fast, less expensive, and, importantly requires a lower blood volume. This assay could be very promissing for evaluating inducible HIV-1 reservoirs in pediatric HIV-1 studies.

碩士
慈濟大學
宗教與人文研究所
101
This research proceeds from inquiring the meaning of Tibetan Prostration. The methodology of Body Phenomenology consults the view of Merleau-Ponty who treat “ the phenomenal body” as “the subjective body”, and the view of “dynamic balance” by Schmitz. Thus, this is also taken as an “operated and experienced” phenomenology. 　　The religious doctrines are “epoché” because the experiences were condensed. The Prostration should be reduced to the situation of body practice. The Prostration, as the preparation of self-cultivation, works with “Somatics”-especially the “experiential anatomy” in body-space exploring to illustrate how to “back to the experience itself”. The process of experience gives the “corporeality” of inner space, and the development of ability of “perceiving”. Finally, the description of corporeality appears on the process of reduction. 　　Researcher found when one perceive the corporeality would force oneself at present time, and that would make oneself aware the Inner-time and Lifetime Mirror-reflect to each other. Meanwhile, the embodiment means what corporeality depends on different intentionality to arrive the experience. In the embodiment of self-cultivation, the Prostration makes these experiences stay Flowing-Time and maintains the Mirror-reflecting in pieces, breaking, and unformed flowing situation. The inner-space could keep distance with Mirror-reflecting and stay unfinished situation, to perceive but do not catch anything. In the end, the Prostration could expand the range of inner-space that allow different things passing, to make it as the preparation of self-cultivation which is like body energy or Emptiness, etc.

Chapter 1 details our investigation into the Diels-Alder reaction between arynes and chiral furans and pyrroles for the synthesis of unsymmetrical [2.2.1] oxabicyclic and azabicyclic scaffolds as single enantiomers. It was discovered that the diastereoselectivity of the aryne Diels-Alder reaction was sensitive to conformational effects that could be exploited to obtain both high yields and dr. Stereoselective synthesis using arynes is an overlooked field, and this contribution represents one of only three such examples in the literature. The desymmetrization of meso [2.2.1] oxabicyclic systems by intramolecular cyclization/ring- opening was studied, and a cationic Rh/t-Bu-Josiphos catalyst was developed that delivered polyclic dihydronaphthalene products in excellent yield and ee. These catalyst conditions were used for the ring-opening of an enantiomerically pure unsymmetrical oxabicyclic alkene, which led to the discovery that ring-opening proceeded with complete reagent control. A regiodivergent resolution was designed that gave pairs of enantiomerically enriched dihydronaphthalenes from unsymmetrical racemic starting materials. In chapter 3, the scope of the regiodivergent resolution was expanded to include the ring-opening of remotely-substituted oxabicyclic alkenes and furan-hetaryne Diels-Alder adducts. The utility ii of the method was demonstrated by using it to synthesize two important API molecules from a single racemic precursor. Finally, chapter 4 describes our lab’s efforts toward the total synthesis of the natural products phorbol and prostratin that features the ring-opening of an unsymmetrical [3.2.1] oxabicycle as the key step. Advanced intermediates (requiring >30 linear steps) were synthesized on gram- scale. The entire carbon framework was successfully installed, and our efforts to complete the synthesis are discussed.

Yes
The membrane-type matrix metalloproteinases (MT-MMPs), an important subgroup of the wider MMP family, demonstrate widespread expression in multiple tumor types, and play key roles in cancer growth, migration, invasion and metastasis. Despite a large body of published research, relatively little information exists regarding evidence for MT-MMP expression and function in metastatic prostate cancer. This review provides an appraisal of the literature describing gene and protein expression in prostate cancer cells and clinical tissue, summarises the evidence for roles in prostate cancer progression, and examines the data relating to MT-MMP function in the development of bone metastases. Finally, the therapeutic potential of targeting MT-MMPs is considered. While MT-MMP inhibition presents a significant challenge, utilisation of MT-MMP expression and proteolytic capacity in prostate tumors is an attractive drug development opportunity.