The role of growth factors, steroid hormones and their receptors in the proliferation of human prostate tumor cells, LNCaP

This thesis deals with a tumor cell line, named LNCaP, which has been derived from a lymph node carcinoma of the human prostate. LNCaP cells show androgen responsive growth. The first aim was to study the possible involvement of growth factors and their receptors in the proliferation of the androgen responsive cell line (chapter 3 to 5). As described before, the prostate is a target organ for steroid hormones such as testosterone. As most of prostate cancers are androgen responsive, endocrine therapy, directed at androgen deprivation, may influence their growth. Androgen deprivation can be assessed by inhibiting the release of luteinizing hormone releasing hormone and/or luteinizing hormone which results in a decrease in testosterone serum levels. One of the ways this can be achieved is by estrogen therapy. Estrogens mimic testosterone in the feedback mechanism thus blocking secretion of luteinizing hormone releasing hormone and luteinizing hormone ahd thereby the production of testicular testosterone. Antiandrogens are substances that prevent androgens from expressing their activity (e.g~ growth induction) at target tissue by blocking androgenreceptor interaction. The second aim of the thesis was to compare the effects of androgens with other steroids and antiandrogens concerning growth regulation and other physiological processes in the androgen responsive prostate tumor cell LNCaP (chapter 6 and 7). Finally, we have considered possible effects on LNCaP cells of suramin, a polyanionic compound which has been described to counteract growth factor activity. The effect of suramin on androgen responsive and growth factor responsive growth of LNCaP cells was studied (chapter 8

Stimulatory effects of antiandrogens on LNCaP human prostate tumor cell growth, EGF-receptor level and acid phosphatase secretion

Abstract LNCaP cells (derived from a lymph node carcinoma of the human prostate) show androgen responsive growth. Progestagens, estradiol and antiandrogens competed with androgens for binding to the androgen receptor in the cells to a higher extent than in other androgen-sensitive systems. Optimal growth (3–4 fold increase in DNA content of 6 day cell cultures vs controls) was observed after addition of the synthetic androgen R1881 (0.1 nM). Both steroidal and non-steroidal antiandrogens did not suppress the androgen responsive growth. At a concentration of 10 nM cyproterone acetate or 100 nM RU 23908, growth was even stimulated to an extent comparable to that observed after addition of androgen. Cyproterone acetate and RU 23908 also increased the number of epidermal growth factor receptors expressed at the cell surface to a comparable level as did the androgen. Like androgens, cyproterone acetate, RU 23908 or estradiol stimulated the secretion per cell of prostate specific acid phosphatase in the culture fluid. In conclusion, antiandrogens can exert striking stimulatory effects on the proliferation of LNCaP cells probably due to a defective androgen receptor system. It is discussed that comparable changes in the specificity of the androgen receptor in prostate cancer cells may give these cells an advantage in growth rate and may contribute to development of tumors characterized as hormone independent

特許ライセンスをめぐる最近の立法動向

markdownabstract__Abstract__ The mitogenic activity of several growth factors on androgen responsive LNCaP human prostate tumor cells was studied. A two-fold stimulation of cell proliferation was observed after a culture period of 6 days in 1 ng EGF/ml, 10 ng TGF-α/ml or 20 ng basic FGF/ml. TGF-β (0.02 ng/ml), which did not affect cell proliferation when added alone to the culture medium, inhibited the EGF- and TGF-α-induced growth. The synthetic androgen R1881 (0.1 nM) stimulated cell proliferation three-fold and increased the number of EGF receptors from 11500 to 28500 sites/cell. One of the mechanisms involved in androgen action on these cells in therefore an increased EGF receptor expression and increased sensitivity to EGF. TGF-β did not directly affect androgen-responsive growth but inhibited the synergistic effect of EGF. A considerable expression of TGFα (precursors) could be demonstrated on the cells by immunohistochemical staining. However the staining intensity was not affected by androgens. These results make it less likely that androgen-responsive growth is mediated by regulation of secretion of an EGF- or TGFga-likely activity, which in turn acts in an autocrine manner to stimulate growth. Estrogens, progestagens and antiandrogens do not inhibit androgen responsive growth of LNCaP cells but have striking growth stimulatory effects, increase EGF receptor level and increase acid phosphatase secretion. LNCaP cells contain a modified androgen receptor system with respect to both steroid specificity and antiandrogen sensitivity. It has recently been shown that the stimulatory effects are due to a mut of the androgen receptor

Transbronchial Cryobiopsy Compared to Forceps Biopsy for Diagnosis of Acute Cellular Rejection in Lung Transplants: Analysis of 63 Consecutive Procedures

BACKGROUND Acute cellular rejection (ACR) is a complication after lung transplantation (LTx). The diagnosis of ACR is based on histologic findings using transbronchial forceps biopsy (FB). However, its diagnostic accuracy is limited because of the small biopsy size and crush artifacts. Transbronchial cryobiopsy (CB) provides a larger tissue size compared with FB. METHODS FB and CB were obtained consecutively during the same bronchoscopy (February 2020-April 2021). All biopsies were scored according to the ISHLT criteria by three pathologists. Interobserver agreement was scored by the kappa index. We assessed the severity of bleeding and the presence of pneumothorax. RESULTS In total, 35 lung transplant recipients were included, and 126 CBs and 315 FBs were performed in 63 consecutive bronchoscopies. ACR (A1-A3, minimal-moderate) was detected in 18 cases (28.6%) by CB, whereas ACR was detected in 3 cases (4.8%) by FB. Moderate and severe bleeding complicated FB and CB procedures in 23 cases (36.5%) and 1 case (1.6%), respectively. Pneumothorax occurred in 6.3% of patients. The interobserver agreement was comparable for both CB and FB. CONCLUSIONS CB provided an improved diagnostic yield for ACR diagnosis, leading to reclassification and changes in treatment strategies in 28.6% of cases. Prospective studies should better define the role of CB after LTx

Distributed Flow Algorithms for Scalable Similarity Visualization

We describe simple yet scalable and distributed algorithms for solving the maximum flow problem and its minimum cost flow variant, motivated by problems of interest in objects similarity visualization. We formulate the fundamental problem as a convex-concave saddle point problem. We then show that this problem can be efficiently solved by a first order method or by exploiting faster quasi-Newton steps. Our proposed approach costs at most O(|E|) per iteration for a graph with |E| edges. Further, the number of required iterations can be shown to be independent of number of edges for the first order approximation method. We present experimental results in two applications: mosaic generation and color similarity based image layouting

Advances in Large Margin Classifiers

this article also provide a website to obtain the dat

Reinforcement Teaching

Meta-learning strives to learn about and improve a student's machine learning algorithm. However, existing meta-learning methods either only work with differentiable algorithms or are hand-crafted to improve one specific component of an algorithm. We develop a unifying meta-learning framework, called Reinforcement Teaching, to improve the learning process of any algorithm. Under Reinforcement Teaching, a teaching policy is learned, through reinforcement, to improve a student's learning. To effectively learn such a teaching policy, we introduce a parametric-behavior embedder that learns a representation of the student's learnable parameters from its input/output behavior. Further, we use learning progress to shape the teacher's reward, allowing it to more quickly maximize the student's performance. To demonstrate the generality of Reinforcement Teaching, we conduct experiments where a teacher learns to significantly improve both reinforcement and supervised learning algorithms, outperforming hand-crafted heuristics and previously proposed parameter representations. Results show that Reinforcement Teaching is capable of not only unifying different meta-learning approaches, but also effectively leveraging existing tools from reinforcement learning research.Comment: First two authors contributed equall

Members of the aquaporin family in the developing pea seed coat include representatives of the PIP, TIP, and NIP subfamilies

Water and nutrients required by developing seeds are mainly supplied by the phloem and have to be released from a maternal parenchyma tissue before being utilized by the filial tissues of embryo and endosperm. To identify aquaporins that could be involved in this process four full-length cDNAs were cloned and sequenced from a cDNA library of developing seed coats of pea (Pisum sativum L.). The cDNA of PsPIP1-1 appeared to be identical to that of clone 7a/TRG-31, a turgor-responsive gene cloned previously from pea roots. PsPIP1-1, PsPIP2-1, and PsTIP1-1, or their possible close homologues, were also expressed in cotyledons of developing and germinating seeds, and in roots and shoots of seedlings, but transcripts of PsNIP-1 were only detected in the seed coat. In mature dry seeds, high hybridization signals were observed with the probe for PsPIP1-1, but transcripts of PsPIP2-1, PsTIP1-1, and PsNIP-1 were not detected. Functional characterization after heterologous expression in Xenopus oocytes showed that PsPIP2-1 and PsTIP1-1 are aquaporins whereas PsNIP-1 is an aquaglyceroporin. PsNIP-1, like several other NIPs, contains a tryptophan residue corresponding with Trp-48 in GlpF (the glycerol facilitator of Escherichia coli) that borders the selectivity filter in the permeation channel. It is suggested that PsPIP1-1 and/or its possible close homologues could play a role in water absorption during seed imbibition, and that PsPIP2-1, possibly together with PsPIP1-1, could be involved in the release of phloem water from the seed coat symplast, which is intimately connected with the release of nutrients for the embryo. Abbreviations: MIPs, major intrinsic proteins; NIPs, nodulin 26-like intrinsic proteins; PIPs, plasma membrane intrinsic proteins; SIPs, small, basic intrinsic proteins; TIPs, tonoplast intrinsic protein

Transbronchial Cryobiopsy Compared to Forceps Biopsy for Diagnosis of Acute Cellular Rejection in Lung Transplants: Analysis of 63 Consecutive Procedures

Background: Acute cellular rejection (ACR) is a complication after lung transplantation (LTx). The diagnosis of ACR is based on histologic findings using transbronchial forceps biopsy (FB). However, its diagnostic accuracy is limited because of the small biopsy size and crush artifacts. Transbronchial cryobiopsy (CB) provides a larger tissue size compared with FB. Methods: FB and CB were obtained consecutively during the same bronchoscopy (February 2020–April 2021). All biopsies were scored according to the ISHLT criteria by three pathologists. Interobserver agreement was scored by the kappa index. We assessed the severity of bleeding and the presence of pneumothorax. Results: In total, 35 lung transplant recipients were included, and 126 CBs and 315 FBs were performed in 63 consecutive bronchoscopies. ACR (A1–A3, minimal–moderate) was detected in 18 cases (28.6%) by CB, whereas ACR was detected in 3 cases (4.8%) by FB. Moderate and severe bleeding complicated FB and CB procedures in 23 cases (36.5%) and 1 case (1.6%), respectively. Pneumothorax occurred in 6.3% of patients. The interobserver agreement was comparable for both CB and FB. Conclusions: CB provided an improved diagnostic yield for ACR diagnosis, leading to reclassification and changes in treatment strategies in 28.6% of cases. Prospective studies should better define the role of CB after LTx