A Real‐World Multicentre Retrospective Study of Paclitaxel‐Bevacizumab and Maintenance Therapy as First‐Line for HER2‐Negative Metastatic Breast Cancer

Bevacizumab in combination with taxanes in HER2‐negative metastatic breast cancer (MBC) patients has shown improved progression‐free survival (PFS), despite the lack of clear overall survival (OS) benefit. We performed a retrospective analysis to evaluate the impact of paclitaxel‐bevacizumab and of maintenance therapy with bevacizumab (BM) and endocrine therapy (ET) in the real‐world practice. We identified 314 HER2‐negative MBC patients treated in 12 cancer centers. Overall, the median PFS and OS were 14 and 40 months, respectively. Among the 254 patients potentially eligible for BM, 183 received BM after paclitaxel discontinuation until progression/toxicity. PFS and OS were improved in patients who had received BM in comparison with those potentially eligible but who did not receive BM (P< 0.0001 and P = 0.001, respectively). Results were confirmed when adjusting for propensity score. Among the 216 hormone‐receptor positive patients eligible for BM, a more favorable PFS and OS were observed when maintenance ET was administered (P < 0.0001). Multivariate analysis showed that PS, BM, number of disease sites and maintenance ET were related to PFS, while response and maintenance ET were related to OS. In hormone‐receptor positive patients, BM produced a significant PFS and a trend towards OS benefit only in absence of maintenance ET (P = 0.0007 and P = 0.06, respectively). In the triple‐negative subgroup, we observed a trend towards a better OS for patients who received BM (P = 0.06), without differences in PFS (P = 0.21). Our results confirmed the efficacy of first‐line paclitaxel‐bevacizumab in real‐world practice; both BM and maintenance ET significantly improved PFS and OS compared to no maintenance therapies. J. Cell. Physiol. 232: 1571–1578, 2017. © 2016 Wiley Periodicals, Inc.     

Antisense oligonucleotides as therapeutic agents.

Antisense oligonucleotides can block the expression of specific target genes involved in the development of human diseases. Therapeutic applications of antisense techniques are currently under investigation in many different fields. The use of antisense molecules to modify gene expression is variable in its efficacy and reliability, raising objections about their use as therapeutic agents. However, preliminary results of several clinical studies demonstrated the safety and to some extent the efficacy of antisense oligodeoxynucleotides (ODNs) in patients with malignant diseases. Clinical response was observed in some patients suffering from ovarian cancer who were treated with antisense targeted against the gene encoding for the protein kinase C-alpha. Some hematological diseases treated with antisense oligos targeted against the bcr/abl and the bcl2 mRNAs have shown promising clinical response. Antisense therapy has been useful in the treatment of cardiovascular disorders such as restenosis after angioplasty, vascular bypass graft occlusion, and transplant coronary vasculopathy. Antisense oligonucleotides also have shown promise as antiviral agents. Several investigators are performing trials with oligonucleotides targeted against the human immunodeficiency virus-1 (HIV-1) and hepatitis viruses. Phosphorothioate ODNs now have reached phase I and II in clinical trials for the treatment of cancer and viral infections, so far demonstrating an acceptable safety and pharmacokinetic profile for continuing their development. The new drug Vitravene, based on a phosphorothioate oligonucleotide designed to inhibit the human cytomegalovirus (CMV), promises that some substantial successes can be reached with the antisense technique.     

Crossing the (Wallace) line: local abundance and distribution of mammals across biogeographic barriers

Past and ongoing vertebrate introductions threaten to rearrange ecological communities in the Indo‐Malay Archipelago, one of Earth's most biodiverse regions. But the consequences of these translocations are difficult to predict. We compared local abundance and distributions in four tropical mammal lineages that have crossed from Asia to Wallacea or New Guinea. The local abundance of macaques (Macaca spp.), which naturally crossed Wallace's Line, was higher in Sulawesi (east of the line; mean = 3.7 individuals per camera station, 95% CI = 2.2: 5.1) than in Borneo (west of the line; mean = 1.1, CI = 0.8: 1.4), but the local abundance of Malay civets (Viverra tangalunga), Rusa deer, and Sus pigs was similar in their native ranges and where they had been introduced by humans east of Wallace's Line. Proximity to rivers increased Malay Civet local abundance and decreased the local abundance of pigs in parts of their introduced ranges (Maluku and New Guinea, respectively), while having no effect on local abundance in their native ranges (Borneo) or other areas where they have been introduced (Sulawesi). That local abundance was higher east of Wallace's Line in just one of four mammal lineages is consistent with findings from plant invasions, where most species have similar abundance in their native and introduced ranges. However, species’ ecology may change as they enter new communities, for example, their patterns of abundance at local scales. This could make it difficult to predict community structure in the face of ongoing species introductions.     

A tale of two eras: Phytoplankton composition influenced by oceanic paleochemistry

We report the results of simple experiments which support the hypothesis that changes in ocean chemistry beginning in the Mesozoic Era resulted in an increase in the nutritional quality per mole of C and per cell of planktonic algal biomass compared to earlier phytoplankton. We cultured a cyanobacterium, a diatom, a dinoflagellate, and a green alga in media mimicking aspects of the chemistry of Palaeozoic and Mesozoic‐Cenozoic oceans. Substantial differences emerged in the quality of algal biomass between the Palaeozoic and Mesozoic‐Cenozoic growth regimes; these differences were strongly affected by interspecific interactions (i.e., the co‐existence of different species alters responses to the chemistry of the medium). The change was in the direction of a Mesozoic‐Cenozoic biomass enriched in protein per mole C, although cells contained less carbon overall. This would lead to a lower C:N ratio. On the assumption that Mesozoic‐Cenozoic grazers’ assimilation of total C was similar to that of their earlier counterparts, their diet would be stoichiometrically closer to their C:N requirement. This, along with an increase in mean cell size among continental shelf phytoplankton, could have helped to facilitate observed evolutionary changes in the Mesozoic marine fauna. In turn, increased grazing pressure would have operated as a selective force for the radiation of phytoplankton clades better equipped with antigrazing capabilities (sensu lato), as found widely in phytoplankton with biomineralization. Our results emphasize potential links between changing seawater chemistry, increased predation pressure and the rise to ecological dominance of chlorophyll a+c algae in Mesozoic oceans. The experiments also suggest a potential role for ocean chemistry in changes of marine trophic structure from the Palaeozoic to the later Mesozoic Era.     

Skeletal muscle metabolism in physiology and in cancer disease

Skeletal muscle is a tissue of high demand and it accounts for most of daily energy consumption. The classical concept of energy metabolism in skeletal muscle has been profoundly modified on the basis of studies showing the influence of additional factors (i.e., uncoupling proteins (UCPs) and peroxisome proliferator activated receptors (PPARs)) controlling parameters, such as substrate availability, cellular enzymes, carrier proteins, and proton leak, able to affect glycolysis, nutrient oxidation, and protein degradation. This extremely balanced system is greatly altered by cancer disease that can induce muscle cachexia with significant deleterious consequences and results in muscle wasting and weakness, delaying or preventing ambulation, and rehabilitation in catabolic patients.     

Dual role of parathyroid hormone in endothelial progenitor cells and marrow stromal mesenchymal stem cells

Hematopoietic stem cells derive regulatory information also from parathyroid hormone (PTH). To explore the possibility that PTH may have a role in regulation of other stem cells residing in bone marrow, such as mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) we assessed the effect of this hormone on the in vitro behavior of MSCs and EPCs. We evidenced that MSCs were much more responsive to PTH than EPCs. PTH increased the proliferation rate of MSCs with a diminution of senescence and apoptosis. Taken together, our results may suggest a protective effect of PTH on MSCs that reduces stress phenomena and preserve genome integrity. At the opposite, PTH did not modify the fate of EPCs in culture. J. Cell. Physiol. 222: 474–480, 2010. © 2009 Wiley‐Liss, Inc.     

Mitral re-repair and right coronary fistula closure: advantage of minimally invasive approach

A 51-year-old man developed severe mitral regurgitation 10 years after previous mitral valve repair; the echocardiographic images showed a remarkable eccentric jet toward posterior wall of left atrium associated with a high degree of pulmonary vein retrograde flow. The coronary arteriography pointed out no pathologic lesions but a coronary fistula from the proximal right coronary to the right atrium. The standard approach was avoided, and a right anterolateral minithoracotomy was chosen, providing an excellent view. Under cardiopulmonary bypass and mild hypothermia, the mitral valve was re-repaired, and a new ring was implanted. After aortic cross-clamp release, the right coronary fistula was closed through the right atrium. The postoperative course was uneventful, and the patient was discharged on the fourth postoperative day. In such a high-risk reintervention and concomitant procedure, we think that this different approach may represent a feasible and reliable alternative.     

An effective method for adenoviral-mediated delivery of small interfering RNA into mesenchymal stem cells

Mesenchymal stem cells (MSCs) promise as a main actor of cell-based therapeutic strategies, due to their intrinsic ability to differentiate along different mesenchymal cell lineages, able to repair the diseased or injured tissue in which they are localized. The application of MSCs in therapies requires an in depth knowledge of their biology and of the molecular mechanisms leading to MSC multilineage differentiation. The knockdown of target genes through small interfering RNA (siRNA) carried by adenoviruses (Ad) represents a valid tool for the study of the role of specific molecules in cell biology. Unfortunately, MSCs are poorly transfected by conventional Ad serotype 5 (Ad5) vectors. We set up a method to obtain a very efficient transduction of rat MSCs with low doses of unmodified Ad5, carrying the siRNA targeted against the mRNA coding for Rb2/p130 (Ad-siRNA-Rb2), which plays a fundamental role in cell differentiation. This method allowed a 95% transduction rate of Ad-siRNA in MSC, along with a siRNA-mediated 85% decrease of Rb2/p130 mRNA and a 70% decrease of Rb2/p130 protein 48 h after transduction with 50 multiplicities of infection (MOIs) of Ad5. The effect on Rb2/p130 protein persisted 15 days after transduction. Finally, Ad-siRNA did not compromise the viability of transduced MSCs neither induced any cell cycle modification. The effective Ad-siRNA-Rb2 we constructed, together with the efficient method of delivery in MSCs we set up, will allow an in depth analysis of the role of Rb2/p130 in MSC biology and multilineage differentiation.