The predictive value of steroid hormone receptor analysis in breast, endometrial and ovarian cancer

The predictive value of female sex steroid, estrogen and progesterone, receptor (ER and PR, respectively) assays in breast, endometrial and ovarian cancer is reviewed with emphasis on comparative aspects of these malignant tumors in relation to their hormone dependency. The endocrine etiology of these three tumor types seems to be at least partly different, and so is the expression of these receptors in normal and malignant tissues of the breast, endometrium and ovary. There is a tendency for decreased receptor concentrations and disappearance of these receptors in association with advancement of these malignancies. There is also a decrease in the presence and concentrations of ER and PR in relation to loss of differentiation in breast and endometrial cancer. Receptor analyses have an established position in the selection of patients with advanced breast cancer for endocrine treatment, and they give promise of a similar application in endometrial cancer and in endometrioid cancer of the ovary. It is not clear whether the disease-free interval is related to the presence or concentrations of ER or PR as such in the tumor tissue. There is better survival in breast cancer patients with receptor-positive tumors, which might be due to a response to endocrine treatment. The same seems to be true for patients with endometrial cancer. Future progress in the application of female sex steroid receptor analyses in breast, endometrial and ovarian cancer needs additional controlled clinical trials and more highly developed receptor assays.     

Rapidly growing breast cancer: results of a retrospective analysis with a study of prognostic factors

Between January 1977 and December 1982, 66 consecutive patients have been treated for unilateral, rapidly progressing, non metastatic breast cancer. They were divided into three groups: Group A (n = 10): tumor whom volume had increased during the 2 months before diagnosis; Group B (n = 30): inflammatory signs (erythema, skin oedema, elevated local temperature) involving less than one half of the breast; Group C (n = 26): inflammatory signs involving more than one half of the breast. All patients where managed similarly: 3 to 4 courses of chemotherapy (CMF: n = 24; AVCF: n = 42), then loco regional irradiation therapy with cobalt 60, followed by maintenance chemotherapy, only if the first chemotherapy had proved effective (CMF: n = 13; AVCF: n = 27). Nine patients with residual tumor after radiotherapy underwent mastectomy with axillary dissection. The actuarial 5 years survival for the whole group is 29%, and respectively 49%, 38% and 9% for the groups A, B and C. The median disease free intervals are 43, 29 and 12 months respectively. Fifteen prognostic factors likely to influence overall survival or disease free survival were evaluated. With univariate analysis, 8 factors were found to be of individual prognostic value: extent of initial erythema, erythema present after initial chemotherapy, erythema present after radiotherapy, non menopaused status, tumor diameter greater than 10 cms, residual breast tumor (clinical or radiographic) after maintenance chemotherapy, supra clavicular adenopathy (N3). Age at the diagnosis, type of chemotherapy, or performance of a radical mastectomy did not influence the prognosis. Multivariate analysis using the Cox-model isolated 3 factors of bad prognosis: erythema involving the whole breast at initial diagnosis, erythema present at the end of initial chemotherapy, N3.     

Combining Vaccines with Conventional Therapies for Cancer

Preclinical and clinical investigations currently underway are employing novel strategies for combining vaccines with conventional and experimental anticancer therapies. To date, the FDA has not approved a therapeutic cancer vaccine. However, the results of recent investigations suggest an increasing role for vaccines in new models of combination therapy for many types of cancer. This article reviews and discusses therapeutic cancer strategies that employ vaccines in combination with local radiation, chemotherapy, hormone therapy, and anti-CTLA-4 mAb. Preclinical studies have shown that certain anticancer agents have immune modulatory effects that result in up-regulation of surface expression of MHC molecules, tumor-associated antigens, or Fas on malignant cells, rendering them more susceptible to immune destruction. Preliminary results of clinical studies using combination strategies have demonstrated a postvaccination antigen cascade, prolonged time to disease progression, and improved overall survival. Several larger randomized trials are ongoing, and more are required to support these findings.     

Synthesis of Indole-Containing 2-Thiobarbituric Acid Derivatives

The synthesis of barbituric acid derivatives containing α-phenylskatyl residues substituted at C(5) is described. The initial compound was α-phenylnorgramine, which had been previously successfully used for the alkylation of a series of CH-acids, in particular, for the synthesis of diethyl-1H-indol-3-yl(phenyl)methylmalonate. This compound has been used to obtain a series of 2-thiobarbituric acid derivatives, which are expected to possess antioxidant, membrane protector, and radioprotector properties.__________Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 1, pp. 29 – 33, January, 2005.     

Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B

Abstract: We have designed and synthesized a new series of azapeptides which act as potential inhibitors of cathepsin B and/or cathepsin K. Their structures are based upon the inhibitory sites of natural cysteine protease inhibitors, cystatins. For the synthesized azapeptides, the equilibrium constants for dissociation of inhibitor–enzyme complex, K_i, were determined. Comparison of these values indicated that all of the azainhibitors act much stronger toward cathepsin B. Z‐Arg‐Leu‐His‐Agly‐Ile‐Val‐OMe ( 7 ) proved to be approximately 500 times more potent for cathepsin B than for cathepsin K. To be able to explain the obtained experimental values we used the molecular dynamics procedures to analyze the interactions between cathepsin B and compound 7 . We also determined the structure of the most potent and selective cathepsin B azainhibitor by means of NMR studies and theoretical calculations. In this report, we describe SAR studies of azapeptide inhibitors indicating the influence of the conformational flexibility of the examined compounds on inhibition of cathepsins B and K.     

Synthesis and anti-tuberculous activity of diesters based on isosteviol and dicarboxylic acids

Diesters based on isosteviol and dicarboxylic acids were synthesized and tested for antituberculous activity. Isosteviol and some of its derivatives exhibit appreciable tuberculostatic properties in vitro, the activity being dependent on the length of the polymethylene spacer connecting two ent-beyeran fragments. The mechanism of the antituberculous action of isosteviol derivatives are discussed. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 9, pp. 12–13, September, 2006.     

Highlights in asthma 2005.

It is usual at the end of a year for top tens to feature large in our collective consciousness. These inevitably include the occasional controversial selection and without fail will overlook a number of gems, whether in the field of literature, art, or science. The approaches to such compilations include personal selections, convening expert committees through to letting the market decide. However, it is well recognised that experts can be wrong and markets distorted. A novel approach to identifying the key publications in the field of medicine, Faculty of 1000 Medicine (http://www.f1000medicine.com), uses faculty evaluations to assign ratings to published papers within topics and categories, bringing a flavour of the dynamism of post hoc peer review to biological sciences that exists in other fields of scholarship. Archives of Disease in Childhood has also developed a market led system of peer evaluation through its web based top ten most read articles feature.     

Alternaria alternata NADP-dependent mannitol dehydrogenase is an important fungal allergen.

BACKGROUND: Alternaria alternata is one of the most important allergenic fungi worldwide. Mannitol dehydrogenase (MtDH) has previously been shown to be a major allergen of Cladosporium herbarum and cross-reactivity has been demonstrated for several fungal allergens. OBJECTIVE: The present study's objective was to clone the MtDH from an A. alternata cDNA library, express and purify the recombinant non-fusion protein and test its IgE-binding properties. Methods A cDNA library prepared from A. alternata hyphae and spores was screened for mannitol dehydrogenase by DNA hybridization with the radioactively labelled C. herbarum homologue as a probe. The resulting clone was sequenced and heterologously expressed in Escherichia coli as a recombinant non-fusion protein, which was purified to homogeneity and analysed for its IgE-binding capacity. RESULTS: The coding sequence of the full-length cDNA clone comprises 798 bp encoding a protein with a molecular mass of 28.6 kDa and a predicted pI of 5.88. Protein sequence analysis revealed an identity of 75% and a homology of 86% between the MtDHs of A. alternata and C. herbarum. The functional mannitol dehydrogenase was expressed in the E. coli strain BL21(DE3) transformed with the vector pMW172 and purified to homogeneity. The enzyme catalyses the NADPH-dependent conversion of d-fructose to d-mannitol. In IgE-ELISA and immunoblots, MtDH is recognized by 41% of A. alternata-allergic patients. In vivo immunoreactivity of the recombinant MtDH was verified by skin prick testing. Finally, inhibition-ELISA experiments confirmed cross-reactivity between the MtDHs of A. alternata and C. herbarum. CONCLUSION: Mannitol dehydrogenase (Alt a 8) represents an important new allergen of the ascomycete A. alternata that might be suitable for improving diagnostic and therapeutic procedures.