Opposing effects of pro- and anti-inflammatory cytokine gene polymorphisms on the risk for breast cancer in western Indian women: a pilot study.

In an earlier study, the genotypes associated with higher level of transforming growth factor-ß1 (TGF-ß1) were found to reduce the risk for breast cancer in western Indian women. This observation implied that gene polymorphisms affecting the levels of pro- and anti-inflammatory cytokines may influence the risk for breast cancer in this population. Hence, we performed genotyping for three more functional single-nucleotide polymorphisms (SNPs) responsible for variations in the levels of cytokines associated with inflammation. To that effect, polymorphisms in genes coding for IL-4 (IL-4 C-590T; rs2243250), IFN-γ (IFN-G A + 874T; rs2430561) and MCP-1 (MCP-1 A-2578G; rs1024611) were examined in premenopausal, healthy women (N = 239) and patients with breast cancer (N = 182) from western India. In carriers of the IL-4*590T allele, a reduced risk for the disease (dominant model; OR = 0.61, 95% CI 0.37-0.98) was seen similar to that seen in TGF-B1*10C carriers. An opposite trend was observed with respect to the alleles associated with higher expression of MCP-1 or IFN-γ. In individuals positive for three or more alleles associated with higher levels of either pro- or anti-inflammatory cytokines, an additive effect on the modulation of risk for the disease was evident (for TGF-B1 & IL-4, OR = 0.33, 95% CI 0.12-0.87; for IFN-G & MCP-1, OR = 2.29, 95% CI 0.95-5.51). In the context of contrasting observations in other populations, these results indicate a significant contribution of anti-inflammatory genotypes in the modulation of risk for breast cancer in western Indian women.

Studies on functional status of circulating lymphocytes in unaffected members from cancer families.

That the inheritance of mutations in tumor susceptibility genes alone cannot determine risk for developing cancer is now well accepted. Immune functions have long been recognized as one of the important risk modifying factors in this regard. In an attempt to develop a multiparametric approach to identify high risk individuals from cancer families, we have examined NK cell function in unaffected members from familial breast cancer families. We have also carried out a parallel study of T lymphocyte functions in these individuals. Our studies demonstrate a significantly lower NK cell activity in members from cancer families. T lymphocyte activity also showed a similar trend, with the unaffected members demonstrating a notably lowered T lymphocyte function. In addition the data from patients reveals differential sensitivity of NK and T lymphocyte function to the disease phenotype. Implications of these observations are discussed.

Immune functions, clinical parameters and hormone receptor status in breast cancer patients.

We have carried out a detailed analysis of the cellular immune functions of breast cancer patients in comparison with healthy controls. A possible correlation between immune and clinical parameters was analysed in 50 breast cancer patients. Immune parameters, natural killer cell and T lymphocyte functions and the numbers of circulating T lymphocytes were analysed against the clinical parameters comprising the tumour burden, the stage of the disease and the expression of hormone receptors on the tumour. In order to analyse the immune function data effectively, low responders were identified with stringent cut-off values. Considerably higher proportions of low responders were found among the patient population. Elevated numbers of circulating T lymphocytes and CD3-directed cytolysis correlated with the expression of oestrogen receptors independently of the clinical/histological parameters.

Premature separation of centromere and aneuploidy: an indicator of high risk in unaffected individuals from familial breast cancer families?

It is estimated that one in every four women with a first-degree relative affected by breast cancer will develop the disease. Recent evidence suggests that susceptibility to breast cancer can be inherited. We have carried out cytogenetic analysis on PHA-stimulated lymphocyte cultures of breast cancer patients (familial and sporadic), patients with benign breast lesions, unaffected individuals from families with a history of breast cancer and healthy controls. A high incidence of premature separation of centromere (PSC) and aneuploidy was observed in a significant proportion of familial breast cancer patients and patients with fibrocystic disease as well as in some unaffected individuals from breast cancer families. These observations are also supported by cytogenetic analysis of EBV-transformed lymphoblastoid cell lines established from some of these individuals. No such aberrations were detected in the controls. Further, most of the affected and unaffected individuals with these two anomalies also exhibited structural chromosomal aberrations of 1q, 6q, 7q, 16q, 18q, or Xq. Based on these observations, we propose that the presence of both PSC and aneuploidy in lymphocyte cultures of unaffected individuals from breast cancer families can be used as an important predictive parameter to determine the risk of developing cancer.

Natural killer cell function and genetic instability in unaffected individuals from breast cancer families.

Several recent reports highlight the importance of modifying factors in determining the risk for cancer of a person carrying a mutant allele of a tumour susceptibility gene. The study of two such risk modifying factors namely, natural killer (NK) cell function and constitutional cytogenetic anomalies in members of families with familial breast cancer is presented in this paper. We observed that, compared to healthy controls, a significant proportion of unaffected persons from breast cancer families not only display lower NK cell function or genetic instability alone, but also in conjunction. The significance of these observations is discussed. We propose that amongst the unaffected members, persons with lower NK cell function as well as constitutive cytogenetic anomalies may be at a higher risk for cancer. The need for a set of suitable biomarkers to identify individuals at high risk from familial breast cancer families has been recognized for many years. Constitutional cytogenetic anomalies, otherwise seen in breast tumours, have also been observed in lymphocyte cultures from unaffected persons from such families. Lowered NK cell function has previously been demonstrated in first degree relatives of cancer patients. Both these parameters have been implicated in determining the risk of developing malignancy. In the present study these aspects have been investigated simultaneously in order to assess their utility as potential biomarkers.

Intramolecular dehydrohalogenation during base-mediated reaction of diols with dihaloalkanes.

Sodium alkoxides of a variety of diols were reacted with dibromoalkanes. It was found that the products of the reaction were alkenyl ethers resulting from intramolecular dehydrohalogenation of the initially formed monobromo ethers.

Truly catalytic and enantioselective pinacol coupling of aryl aldehydes mediated by chiral Ti(III) complexes.

A variety of chiral Ti(IV) complexes were reduced in situ with zinc in acetonitrile. The resulting chiral Ti(III) complexes were found to catalyze the pinacol coupling reaction stereoselectively. The best results were obtained from the Ti-SALEN complex, which was found to be an efficient catalyst at 10 mol % concentration. Various aromatic aldehydes were coupled to obtain chiral hydrobenzoin derivatives with high diastereoselectivity and enantioselectivity. A plausible mechanism is proposed that rationalizes the stereochemical outcome of the reaction.

Quantitation of tail lesions in vaccinia-infected mice.

When mice were infected with vaccinia virus via the tail vein, the number of lesions was influenced by the injection site. A site 3 cm from the base of the tail is of greatest practical value.

Concanavalin A-induced electrokinetic changes and redistribution of receptors in mouse thymocytes.

Thymocytes are known to consist of mature and immature cells. The assessment of Con A-induced changes in electrophoretic mobilities (EPM) and receptor redistribution in thymocytes of AKR mice revealed two distinct sub-populations of cells. Sub-population A showed receptor redistribution and increase in EPM at low concentrations of Con A (5 micrograms/ml). Majority of these cells showed two sets of sequentially reacting receptor sites for the lectin. Cells belonging to sub-population B, in contrast, required higher concentrations (15-25 micrograms/ml) of Con A for the redistribution of receptors. Second set of receptors, reacting with Con A after the redistribution of the first set, could not be detected on these cells. High concentrations of Con A inhibited receptor mobility on all the thymocytes. The receptor redistributional profile of cells in the sub-population A was similar to that of mature splenic T-cells while cells in sub-population B resembled the immature leukaemic cells in this respect. These investigations provide an additional parameter to study cellular heterogeneity in thymus.

A dissolution rate apparatus for the prediction of initial drug absorption patterns in beagles: tolbutamide tablets.

An apparatus utilizing liquid turbulence to simulate hydrodynamic conditions generated by gastrointestinal peristalsis was designed to estimate drug release from solid oral dosage forms; This turbulence was achieved through special arrangements of a pipetting pump to a dissolution chamber. By adjusting the flow rate of the pump to deliver and withdraw a fixed volume of dissolution medium per minute, a correlation was developed between dissolution rates and absorption patterns in beagles of two commerical tolbutamide tablets, A and B, and a micronized tolbutamide suspensionmon the basis of this relationship, it was possible to predict the initial absorption patterns of two misformulated tablets, C and D.

Impaired T lymphocyte function and differential cytokine response pattern in members from cancer families.

In an attempt to understand the basis of lowered natural killer (NK) and T cell functions in unaffected members from cancer families, we investigated cytotoxic T lymphocyte function (CD3-directed lysis) and the ability of the lymphocytes to respond to cytokines such as IL-2, IFN-alpha and IL-12. We observed lower CD3-mediated cytotoxic activity in these individuals supported by significantly lower numbers of circulating CD3+ lymphocytes. The cytokine treatment studies revealed impaired response to IFN-alpha and IL-12 in unaffected members and breast cancer patients. The observations presented herein not only reinforce our earlier finding that lower NK and T lymphocyte function may be a feature of cancer families, but also suggest that such impaired responses may be one of the factors contributing to lower cytotoxic potential of the circulating lymphocytes.

The relative bioavailability of a commercial propranolol hydrochloride tablet in man.

A relative bioavailability study of conventional tablet of propranolol hydrochloride was conducted in a group of 18 healthy volunteers employing the innovator's product as the reference tablet formation. Based on plasma levels of propranolol for the 24 h following administration of 2 x 40 mg oral propranolol hydrochloride tablets, the relative extent of availability was shown to be 100.8 per cent for the test tablet formulation; no significant differences were detected between formulations with respect to any of the pharmacokinetic parameters examined. Large intersubject variations in plasma propranolol concentrations and the subsequently calculated areas under the plasma concentration/time curves were attributed to substantial presystemic biotransformation differences.

Production of interleukin-2 and expression of tac antigen in Hodgkin disease.

Phytohemagglutinin (PHA)- induced Interleukin-2 (IL-2) production by peripheral blood mononuclear cells was studied in 28 untreated patients with Hodgkin Disease (HD). A group of 28 patients were also investigated for the expression of Tac antigen in the resting stage of lymphocytes and after activation with PHA and mixed leukocyte culture (using anti-Tac monoclonal antibody). The blastogenic response to PHA and IL-2 production by lymphocytes of HD patients was significantly lower than that of normal lymphocytes. Production of IL-2 appeared to be severely affected in 14 of 28 HD patients who also showed PHA response less than the normal range. The Tac antigen expression was found to be lower in PHA-stimulated but not alloantigen-stimulated lymphocytes from the HD patients. No correlation was observed between the levels of IL-2 production, Tac antigen expression, and blastogenic response to PHA or allogeneic cells and the stage of disease when tested in the same patients.