Spinach, a cyclops, and the search for a cure for prostate cancer

Abstract only availableOther than skin cancer, prostate cancer is the most prevalent form of cancer in men. The likelihood of developing prostate cancer increases with age; so that nearly every male will die with some form of prostate cancer though most likely not from the cancer itself. Prostate cancer is regulated by endocrine and dietary factors, as well as genetic predisposition. In the male reproductive tract, Sonic Hedgehog (Shh) signaling is necessary for the development of the prostate. It has also been found to be extremely important in the growth of a number of tumor types including prostate cancer, basal cell carcinoma (skin cancer), medulloblastoma, glioma, sarcoma, tumors of the digestive tract, small cell lung cancer and pancreatic carcinoma. The Lubahn lab has been studying the roles of Estrogen Receptors and estrogenic compounds on prostate cancer, and has recently used a series of phytoestrogens, natural estrogens found in plants, to inhibit the hedgehog-signaling pathway. One natural product, cyclopamine, is able to inhibit the pathway and has been shown to inhibit prostate cancer cell growth both in vitro and in vivo xenograft models. Additionally, some flavanoid compounds in spinach have been found to have a similar chemical structure to several other phytoestrogens that have been shown to have preventative effects on prostate cancer. A competitive binding assay was performed using various doses of cyclopamine and an unpurified spinach extract to determine Kd for both compounds to ER alpha and ER beta. The compounds were also tested in the NIH-3T3 Shh Light II cells, which have a stably transfected Gli-Luciferase reporter, to see if they downregulated the hedgehog signaling pathway.Food for the 21st Century Undergraduate Research Program in Nutritional Science

Non-operative treatment of common finger injuries

Finger fractures are common injuries with a wide spectrum of presentation. Although a vast majority of these injuries may be treated non-operatively with gentle reduction, appropriate splinting, and careful follow-up, health care providers must recognize injury patterns that require more specialized care. Injuries involving unstable fracture patterns, intra-articular extension, or tendon function tend to have suboptimal outcomes with non-operative treatment. Other injuries including terminal extensor tendon injuries (mallet finger), stable non-articular fractures, and distal phalanx tuft fractures are readily treated by conservative means, and in general do quite well. Appropriate understanding of finger fracture patterns, treatment modalities, and injuries requiring referral is critical for optimal patient outcomes

High order amplitude equation for steps on creep curve

We consider a model proposed by one of the authors for a type of plastic instability found in creep experiments which reproduces a number of experimentally observed features. The model consists of three coupled non-linear differential equations describing the evolution of three types of dislocations. The transition to the instability has been shown to be via Hopf bifurcation leading to limit cycle solutions with respect to physically relevant drive parameters. Here we use reductive perturbative method to extract an amplitude equation of up to seventh order to obtain an approximate analytic expression for the order parameter. The analysis also enables us to obtain the bifurcation (phase) diagram of the instability. We find that while supercritical bifurcation dominates the major part of the instability region, subcritical bifurcation gradually takes over at one end of the region. These results are compared with the known experimental results. Approximate analytic expressions for the limit cycles for different types of bifurcations are shown to agree with their corresponding numerical solutions of the equations describing the model. The analysis also shows that high order nonlinearities are important in the problem. This approach further allows us to map the theoretical parameters to the experimentally observed macroscopic quantities.Comment: LaTex file and eps figures; Communicated to Phys. Rev.

CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk

The length of the polymorphic CAG repeat in the N-terminal of the androgen receptor (AR) gene is inversely correlated with the transactivation function of the AR. Some studies have indicated that short CAG repeats are related to higher risk of prostate cancer. We performed a case–control study to investigate relations between CAG repeat length and prostate cancer risk, tumour grade, tumour stage, age at diagnosis and response to endocrine therapy. The study included 190 AR alleles from prostate cancer patients and 186 AR alleles from female control subjects. All were whites from southern Sweden. The frequency distribution of CAG repeat length was strikingly similar for cases and controls, and no significant correlation between CAG repeat length and prostate cancer risk was detected. However, for men with non-hereditary prostate cancer (n = 160), shorter CAG repeats correlated with younger age at diagnosis (P = 0.03). There were also trends toward associations between short CAG repeats and high grade (P = 0.07) and high stage (P = 0.07) disease. Furthermore, we found that patients with long CAG repeats responded better to endocrine therapy, even after adjusting for pretreatment level of prostate-specific antigen and tumour grade and stage (P = 0.05). We conclude that short CAG repeats in the AR gene correlate with young age at diagnosis of prostate cancer, but not with higher risk of the disease. Selection of patients with early onset prostate cancer in case–control studies could therefore lead to an over-estimation of the risk of prostate cancer for men with short CAG repeats. An association between long CAG repeats and good response to endocrine therapy was also found, but the mechanism and clinical relevance are unclear. © 1999 Cancer Research Campaig

Allosteric Modulators of Steroid Hormone Receptors : Structural Dynamics and Gene Regulation

Peer reviewedPublisher PD

A single base mutation in the androgen receptor gene causes androgen insensitivity in the testicular feminized rat.

The complete form of androgen insensitivity is an inherited X-linked syndrome in which genetic males fail to undergo masculinization in utero due to defective functioning of the androgen receptor (AR). The molecular basis of androgen insensitivity was investigated in the testicular feminized (Tfm) rat with this syndrome. AR mRNA size and amount, as well as nuclear AR protein revealed by immunocytochemistry, suggested normal expression of the AR gene in the Tfm rat. Sequence analysis of the AR coding region from Tfm and wild-type littermate male rats revealed a single transition mutation, guanine to adenine, within exon E, changing arginine 734 to glutamine within the steroid-binding domain of the AR. This arginine is highly conserved among the family of nuclear receptors and may be part of a phosphorylation recognition site. A recreated mutant AR (Arg734----Gln) expressed in COS cells had only 10-15% of the androgen-binding capacity of wild-type AR; the reduced androgen-binding capacity was similar to that of AR in tissue extracts of the Tfm rat. Stimulation of transcriptional activity by the recreated mutant AR was reduced relative to wild-type AR in cotransfection assays in CV1 cells using as reporter plasmid the mouse mammary tumor virus promoter linked to the chloramphenicol acetyltransferase gene. Thus, arginine 734 appears essential for normal AR function both in androgen binding and transcriptional activation. Absence of these functions results in androgen insensitivity and lack of male sexual development

Severe forms of partial androgen insensitivity syndrome due to p.L830F novel mutation in androgen receptor gene in a Brazilian family

<p>Abstract</p> <p>Background</p> <p>The androgen insensitivity syndrome may cause developmental failure of normal male external genitalia in individuals with 46,XY karyotype. It results from the diminished or absent biological action of androgens, which is mediated by the androgen receptor in both embryo and secondary sex development. Mutations in the androgen receptor gene, located on the X chromosome, are responsible for the disease. Almost 70% of 46,XY affected individuals inherited mutations from their carrier mothers.</p> <p>Findings</p> <p>Molecular abnormalities in the androgen receptor gene in individuals of a Brazilian family with clinical features of severe forms of partial androgen insensitivity syndrome were evaluated. Seven members (five 46,XY females and two healthy mothers) of the family were included in the investigation. The coding exons and exon-intron junctions of androgen receptor gene were sequenced. Five 46,XY members of the family have been found to be hemizygous for the c.3015C>T nucleotide change in exon 7 of the androgen receptor gene, whereas the two 46,XX mothers were heterozygote carriers. This nucleotide substitution leads to the p.L830F mutation in the androgen receptor.</p> <p>Conclusions</p> <p>The novel p.L830F mutation is responsible for grades 5 and 6 of partial androgen insensitivity syndrome in two generations of a Brazilian family.</p