Role of traditional and new biomarkers in breast carcinogenesis

In recent decades, several biomarkers have been investigated as predictors of breast cancer risk, development, prognosis and treatment efficacy

Anharmonic calculations of vibrational spectra for molecular adsorbates: A divide-and-conquer semiclassical molecular dynamics approach

The vibrational spectroscopy of adsorbates is becoming an important investigation tool for catalysis and material science. This paper presents a semiclassical molecular dynamics method able to reproduce the vibrational energy levels of systems composed by molecules adsorbed on solid surfaces. Specifically, we extend our divide-and-conquer semiclassical method for power spectra calculations to gas-surface systems and interface it with plane-wave electronic structure codes. The Born-Oppenheimer classical dynamics underlying the semiclassical calculation is full dimensional, and our method includes not only the motion of the adsorbate but also those of the surface and the bulk. The vibrational spectroscopic peaks related to the adsorbate are accounted together with the most coupled phonon modes to obtain spectra amenable to physical interpretations. We apply the method to the adsorption of CO, NO, and H2O on the anatase-TiO2 (101) surface. We compare our semiclassical results with the single-point harmonic estimates and the classical power spectra obtained from the same trajectory employed in the semiclassical calculation. We find that CO and NO anharmonic effects of fundamental vibrations are similarly reproduced by the classical and semiclassical dynamics and that H2O adsorption is fully and properly described in its overtone and combination band relevant components only by the semiclassical approach

Elective surgery for colorectal cancer in the aged: a clinical-economical evaluation.

A series of 56 consecutive patients, referred for surgery to a specialized institute, had elective laparotomies with various surgical procedures aimed at curing locoregional colorectal cancer. Data defining patient and tumour-related preoperative, operative and postoperative variables, including costs, were collected. The study group was divided into two age groups (< 65 vs > or = 65 years), which were similar in terms of patient- and tumour-related variables. Differences were not statistically significant (Pounds 440; 95% exact CI; Pounds -50; 1800). There is no evidence to suggest that there are any total charge differences in treating the two age groups, as confirmed by the cost analysis

Molecular basis of autotrophic vs mixotrophic growth in Chlorella sorokiniana

In this work, we investigated the molecular basis of autotrophic vs. mixotrophic growth of Chlorella sorokiniana, one of the most productive microalgae species with high potential to produce biofuels, food and high value compounds. To increase biomass accumulation, photosynthetic microalgae are commonly cultivated in mixotrophic conditions, adding reduced carbon sources to the growth media. In the case of C. sorokiniana, the presence of acetate enhanced biomass, proteins, lipids and starch productivity when compared to autotrophic conditions. Despite decreased chlorophyll content, photosynthetic properties were essentially unaffected while differential gene expression profile revealed transcriptional regulation of several genes mainly involved in control of carbon flux. Interestingly, acetate assimilation caused upregulation of phosphoenolpyruvate carboxylase enzyme, enabling potential recovery of carbon atoms lost by acetate oxidation. The obtained results allowed to associate the increased productivity observed in mixotrophy in C. sorokiniana with a different gene regulation leading to a fine regulation of cell metabolism

Assessment of submicroscopic genetic lesions by single nucleotide polymorphism arrays in a child with acute myeloid leukemia and FLT3-internal tandem duplication

The same FLT3-internal tandem duplication (ITD) positive clone was detected at diagnosis and relapse, but not at birth, in a child with M1 acute myeloid leukemia. Single nucleotide polymorphism arrays demonstrated that chromosome 13 acquired uniparental disomy, in association with del(9q), represented a progressive event in the course of the disease, and it was responsible for the homozygous FLT3-ITD at relapse

Neoadjuvant eribulin mesylate following anthracycline and taxane in triple negative breast cancer: Results from the HOPE study

Background Eribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant chemotherapy. Methods Patients with primary triple negative breast cancer 2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study. Results In stage I of the study 13 women were enrolled, median age 43 years, tumor size 2–5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of β-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR. Conclusions Despite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of β-catenin pathway core proteins, supposedly outside the domain of epithelial–mesenchymal transition, claims for further investigation. Trial registration EU Clinical Trial Register, EudraCT number 2012-004956-12

Metabolic gatekeeper function of B-lymphoid transcription factors.

B-lymphoid transcription factors, such as PAX5 and IKZF1, are critical for early B-cell development, yet lesions of the genes encoding these transcription factors occur in over 80% of cases of pre-B-cell acute lymphoblastic leukaemia (ALL). The importance of these lesions in ALL has, until now, remained unclear. Here, by combining studies using chromatin immunoprecipitation with sequencing and RNA sequencing, we identify a novel B-lymphoid program for transcriptional repression of glucose and energy supply. Our metabolic analyses revealed that PAX5 and IKZF1 enforce a state of chronic energy deprivation, resulting in constitutive activation of the energy-stress sensor AMPK. Dominant-negative mutants of PAX5 and IKZF1, however, relieved this glucose and energy restriction. In a transgenic pre-B ALL mouse model, the heterozygous deletion of Pax5 increased glucose uptake and ATP levels by more than 25-fold. Reconstitution of PAX5 and IKZF1 in samples from patients with pre-B ALL restored a non-permissive state and induced energy crisis and cell death. A CRISPR/Cas9-based screen of PAX5 and IKZF1 transcriptional targets identified the products of NR3C1 (encoding the glucocorticoid receptor), TXNIP (encoding a glucose-feedback sensor) and CNR2 (encoding a cannabinoid receptor) as central effectors of B-lymphoid restriction of glucose and energy supply. Notably, transport-independent lipophilic methyl-conjugates of pyruvate and tricarboxylic acid cycle metabolites bypassed the gatekeeper function of PAX5 and IKZF1 and readily enabled leukaemic transformation. Conversely, pharmacological TXNIP and CNR2 agonists and a small-molecule AMPK inhibitor strongly synergized with glucocorticoids, identifying TXNIP, CNR2 and AMPK as potential therapeutic targets. Furthermore, our results provide a mechanistic explanation for the empirical finding that glucocorticoids are effective in the treatment of B-lymphoid but not myeloid malignancies. Thus, B-lymphoid transcription factors function as metabolic gatekeepers by limiting the amount of cellular ATP to levels that are insufficient for malignant transformation

Is it time to test metformin in breast cancer clinical trials?

Several studies have identified an increased risk of cancer in type 2 diabetic patients and this is in accordance with the hypothesis that increased insulin levels might promote cancer. Thus, there is a great interest in exploring the possibility that antidiabetic therapies lowering insulin levels could decrease cancer incidence or cancer-related mortality. Recent observational studies have shown that metformin, an oral safe and well-tolerated insulin-sensitizer antidiabetic drug, has been associated with reduced cancer risk. Recently, several preclinical studies have evaluated the effect of metformin in vivo on nude mice and showed a significant reduction of both breast epithelial cell proliferation and protein synthesis. Further investigations in the clinical setting are well-supported by the promising results obtained thus far. At the European Institute of Oncology, the Division of Cancer Prevention and Genetics is planning to conduct a clinical trial to evaluate the activity of metformin on tumor cell proliferation in breast cancer patients undergoing surgery. It will be a presurgical randomized, double blind, placebo-controlled phase II biomarker trial: 100 histologically confirmed breast cancer patients will be randomly assigned to metformin (850 mg twice/daily) or placebo for 28 + 7 days till surgery to assess drug activity on tumor proliferation, as measured by Ki-67. The confirmation of the efficacy of metformin on cancer cell proliferation may lead the way to larger chemoprevention clinical trials. (Cancer Epidemiol Biomarkers Prev 2009;18(3):701–5