Gene expression profiles derived from fine needle aspiration correlate with response to systemic chemotherapy in breast cancer

BACKGROUND: Drug resistance in breast cancer is a major obstacle to successful chemotherapy. In this study we used cDNA microarray technology to examine gene expression profiles obtained from fine needle aspiration (FNA) of primary breast tumors before and after systemic chemotherapy. Our goal was to determine the feasibility of obtaining representative expression array profiles from limited amounts of tissue and to identify those expression profiles that correlate with treatment response. METHODS: Repeat presurgical FNA samples were taken from six patients who were to undergo primary surgical treatment. Additionally, a group of 10 patients who were to receive neoadjuvant chemotherapy underwent two FNAs before chemotherapy (adriamycin 60 mg/m(2) and cyclophosphamide 600 mg/m(2)) followed by another FNA on day 21 after the first cycle. Total RNA was amplified with T7 Eberwine's procedure and labeled cDNA was hybridized onto a 7600-feature glass cDNA microarray. RESULTS: We identified candidate gene expression profiles that might distinguish tumors with complete response to chemotherapy from tumors that do not respond, and found that the number of genes that change after one cycle of chemotherapy was 10 times greater in the responding group than in the non-responding group. CONCLUSION: This study supports the suitability of FNA-derived cDNA microarray expression profiling of breast cancers as a comprehensive genomic approach for studying the mechanisms of drug resistance. Our findings also demonstrate the potential of monitoring post-chemotherapy changes in expression profiles as a measure of pharmacodynamic effect and suggests that these approaches might yield useful results when validated by larger studies

The effect of early pregnancy following chemotherapy on disease relapse and foetal outcome in women treated for gestational trophoblastic tumours

Little literature exists on the safety of early pregnancy following chemotherapy. Here we assess the rate of relapse and foetal outcome in women who have completed single and multi-agent chemotherapy for gestational trophoblastic tumours. The records of 1532 patients treated for persistent gestational trophoblastic tumours at Charing Cross Hospital between 1969 and 1998 were reviewed. Patients were defined as receiving single agent or multi-agent treatment. Relapse rates and foetal outcome were reviewed in the 230 patients who became pregnant within 12 months of completing chemotherapy. In the single agent group 153 (22%) of 691 patients conceived early. Three subsequently relapsed. In the multi-agent group, 77 (10%) of 779 patients conceived early, two then relapsed. Relapse rates were 2% (3 out of 153) and 2.5% (2 out of 77) for each group compared to 5% and 5.6% in the comparative non-pregnant groups. Outcomes of 230 early pregnancies: 164 (71%) delivered at full term, 35 (15%) terminations, 26 (11%) spontaneous abortions, three (1.3%) new hydatidiform moles and two (1%) stillbirths. Early pregnancies were more common in the single agent group (P<0.001), but spontaneous miscarriages and terminations were more likely to occur in the multi-agent group (P=0.04 and 0.03, respectively). Of the full-term pregnancies, three (1.8%) babies were born with congenital abnormalities. Patients in either group who conceive within 12 months of completing chemotherapy are not at increased risk of relapse. Though, we still advise avoiding pregnancy within 12 months of completing chemotherapy, those that do conceive can be reassured of a likely favourable outcome

Limited redundancy in genes regulated by Cyclin T2 and Cyclin T1

<p>Abstract</p> <p>Background</p> <p>The elongation phase, like other steps of transcription by RNA Polymerase II, is subject to regulation. The positive transcription elongation factor b (P-TEFb) complex allows for the transition of mRNA synthesis to the productive elongation phase. P-TEFb contains Cdk9 (Cyclin-dependent kinase 9) as its catalytic subunit and is regulated by its Cyclin partners, Cyclin T1 and Cyclin T2. The HIV-1 Tat transactivator protein enhances viral gene expression by exclusively recruiting the Cdk9-Cyclin T1 P-TEFb complex to a RNA element in nascent viral transcripts called TAR. The expression patterns of Cyclin T1 and Cyclin T2 in primary monocytes and CD4⁺T cells suggests that Cyclin T2 may be generally involved in expression of constitutively expressed genes in quiescent cells, while Cyclin T1 may be involved in expression of genes up-regulated during macrophage differentiation, T cell activation, and conditions of increased metabolic activity To investigate this issue, we wished to identify the sets of genes whose levels are regulated by either Cyclin T2 or Cyclin T1.</p> <p>Findings</p> <p>We used shRNA lentiviral vectors to stably deplete either Cyclin T2 or Cyclin T1 in HeLa cells. Total RNA extracted from these cells was subjected to cDNA microarray analysis. We found that 292 genes were down- regulated by depletion of Cyclin T2 and 631 genes were down-regulated by depletion of Cyclin T1 compared to cells transduced with a control lentivirus. Expression of 100 genes was commonly reduced in either knockdown. Additionally, 111 and 287 genes were up-regulated when either Cyclin T2 or Cyclin T1 was depleted, respectively, with 45 genes in common.</p> <p>Conclusions</p> <p>These results suggest that there is limited redundancy in genes regulated by Cyclin T1 or Cyclin T2.</p

Glutamate regulation of calcium and IP3 oscillating and pulsating dynamics in astrocytes

Recent years have witnessed an increasing interest in neuron-glia communication. This interest stems from the realization that glia participates in cognitive functions and information processing and is involved in many brain disorders and neurodegenerative diseases. An important process in neuron-glia communications is astrocyte encoding of synaptic information transfer: the modulation of intracellular calcium dynamics in astrocytes in response to synaptic activity. Here, we derive and investigate a concise mathematical model for glutamate-induced astrocytic intracellular Ca2+ dynamics that captures the essential biochemical features of the regulatory pathway of inositol 1,4,5-trisphosphate (IP3). Starting from the well-known two-state Li-Rinzel model for calcium-induced-calcium release, we incorporate the regulation of the IP3 production and phosphorylation. Doing so we extended it to a three-state model (referred as the G-ChI model), that could account for Ca2+ oscillations triggered by endogenous IP3 metabolism as well as by IP3 production by external glutamate signals. Compared to previous similar models, our three-state models include a more realistic description of the IP3 production and degradation pathways, lumping together their essential nonlinearities within a concise formulation. Using bifurcation analysis and time simulations, we demonstrate the existence of new putative dynamical features. The cross-couplings between IP3 and Ca2+ pathways endows the system with self-consistent oscillator properties and favor mixed frequency-amplitude encoding modes over pure amplitude modulation ones. These and additional results of our model are in general agreement with available experimental data and may have important implications on the role of astrocytes in the synaptic transfer of information.Comment: 42 pages, 16 figures, 1 table. Figure filenames mirror figure order in the paper. Ending "S" in figure filenames stands for "Supplementary Figure". This article was selected by the Faculty of 1000 Biology: "Genevieve Dupont: Faculty of 1000 Biology, 4 Sep 2009" at http://www.f1000biology.com/article/id/1163674/evaluatio