Adjuvant therapy for locally advanced renal cell cancer: A systematic review with meta-analysis

<p>Abstract</p> <p>Background</p> <p>Many adjuvant trials have been undertaken in an attempt to reduce the risk of recurrence among patients who undergo surgical resection for locally advanced renal cancer. However, no clear benefit has been identified to date. This systematic review was conducted to examine the exact role of adjuvant therapy in renal cancer setting.</p> <p>Methods</p> <p>Randomized controlled trials were searched comparing adjuvant therapy (chemotherapy, vaccine, immunotherapy, biochemotherapy) versus no active treatment after surgery among renal cell cancer patients. Outcomes were overall survival (OS), disease-free survival (DFS), and severe toxicities. Risk ratios (RR), hazard ratios (HR) and 95% confidence intervals were calculated using a fixed-effects meta-analysis. Heterogeneity was measured by I². Different strategies of adjuvant treatment were evaluated separately.</p> <p>Results</p> <p>Ten studies (2,609 patients) were included. Adjuvant therapy provided no benefits in terms of OS (HR 1.07; 95%CI 0.89 to 1.28; P = 0.48 I²= 0%) or DFS (HR 1.03; 95%CI 0.87 to 1.21; P = 0.77 I²= 15%) when compared to no treatment. No subgroup analysis (immunotherapy, vaccines, biochemotherapy and hormone therapy) had relevant results. Toxicity evaluation depicted a significantly higher frequency of serious adverse events in the adjuvant group.</p> <p>Conclusions</p> <p>This analysis provided no support for the hypothesis that the agents studied provide any clinical benefit for renal cancer patients although they increase the risk of toxic effects. Randomized trials are underway to test targeted therapies, which might open a new therapeutic frontier. Until these trials yield results, no adjuvant therapy can be recommended for patients who undergo surgical resection for renal cell cancer.</p

A Chromosomal Inversion Unique to the Northern White-Cheeked Gibbon

The gibbon family belongs to the superfamily Hominoidea and includes 15 species divided into four genera. Each genus possesses a distinct karyotype with chromosome numbers varying from 38 to 52. This diversity is the result of numerous chromosomal changes that have accumulated during the evolution of the gibbon lineage, a quite unique feature in comparison with other hominoids and most of the other primates. Some gibbon species and subspecies rank among the most endangered primates in the world. Breeding programs can be extremely challenging and hybridization plays an important role within the factors responsible for the decline of captive gibbons. With less than 500 individuals left in the wild, the northern white-cheeked gibbon (Nomascus leucogenys leucogenys, NLE) is the most endangered primate in a successful captive breeding program. We present here the analysis of an inversion that we show being specific for the northern white-cheeked gibbon and can be used as one of the criteria to distinguish this subspecies from other gibbon taxa. The availability of the sequence spanning for one of the breakpoints of the inversion allows detecting it by a simple PCR test also on low quality DNA. Our results demonstrate the important role of genomics in providing tools for conservation efforts

Lichen rehydration in heavy metal polluted environments: Pb modulates the oxidative response of both Ramalina farinacea thalli and its isolated microalgae

Lichens are adapted to desiccation/rehydration and accumulate heavy metals, which induce ROS especially from the photobiont photosynthetic pigments. Although their mechanisms of abiotic stress tolerance are still to be unravelled, they seem related to symbionts' reciprocal upregulation of antioxidant systems. With the aim to study the effect of Pb on oxidative status during rehydration, the kinetics of intracellular ROS, lipid peroxidation and chlorophyll autofluorescence of whole Ramalina farinacea thalli and its isolated microalgae (Trebouxia TR1 and T. TR9) was recorded. A genetic characterization of the microalgae present in the thalli used was also carried out in order to assess possible correlations among the relative abundance of each phycobiont, their individual physiological responses and that of the entire thallus. Unexpectedly, Pb decreased ROS and lipid peroxidation in thalli and its phycobionts, associated with a lower chlorophyll autofluorescence. Each phycobiont showed a particular pattern, but the oxidative response of the thallus paralleled the TR1's, agreeing with the genetic identification of this strain as the predominant phycobiont. We conclude that: (1) the lichen oxidative behaviour seems to be modulated by the predominant phycobiont and (2) Pb evokes in R. farinacea and its phycobionts strong mechanisms to neutralize its own oxidant effects along with those of rehydration

The centrosome and spindle as a ribonucleoprotein complex

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Chromosome Research 19 (2011): 367-376, doi:10.1007/s10577-011-9186-7.The presence of nucleic acids in centrosomes and the spindle have been proposed, observed, and reported since the 1950s. Why did the subject remain, perhaps even until today, such a controversial issue? The explanation is manifold, and includes legitimate concern over contamination from other cellular compartments in biochemical preparations. With a typically high background of cytoplasmic ribosomes, even microscopic images of stained intact cells could be difficult to interpret. Also, evidence for RNA and DNA in centrosomes accumulated for approximately 40 years but was interspersed with contradictory studies, primarily regarding the presence of DNA (reviewed in Johnson and Rosenbaum, 1991; Marshall and Rosenbaum, 2000). Perhaps less tangible but still a likely cause for lingering controversy is that the presence of nucleic acids in the spindle or centrosomes will require us to look differently at these structures from a functional, and more to the point, evolutionary standpoint.This work was supported by grants from the NIH (GM088503) and NSF (MCB0843092) to MCA

Risk of chronic kidney disease after cancer nephrectomy.

The incidence of early stage renal cell carcinoma (RCC) is increasing and observational studies have shown equivalent oncological outcomes of partial versus radical nephrectomy for stage I tumours. Population studies suggest that compared with radical nephrectomy, partial nephrectomy is associated with decreased mortality and a lower rate of postoperative decline in kidney function. However, rates of chronic kidney disease (CKD) in patients who have undergone nephrectomy might be higher than in the general population. The risks of new-onset or accelerated CKD and worsened survival after nephrectomy might be linked, as kidney insufficiency is a risk factor for cardiovascular disease and mortality. Nephron-sparing approaches have, therefore, been proposed as the standard of care for patients with type 1a tumours and as a viable option for those with type 1b tumours. However, prospective data on the incidence of de novo and accelerated CKD after cancer nephrectomy is lacking, and the only randomized trial to date was closed prematurely. Intrinsic abnormalities in non-neoplastic kidney parenchyma and comorbid conditions (including diabetes mellitus and hypertension) might increase the risks of CKD and RCC. More research is needed to better understand the risk of CKD post-nephrectomy, to develop and validate predictive scores for risk-stratification, and to optimize patient management

Ancient and Recent Adaptive Evolution of Primate Non-Homologous End Joining Genes

In human cells, DNA double-strand breaks are repaired primarily by the non-homologous end joining (NHEJ) pathway. Given their critical nature, we expected NHEJ proteins to be evolutionarily conserved, with relatively little sequence change over time. Here, we report that while critical domains of these proteins are conserved as expected, the sequence of NHEJ proteins has also been shaped by recurrent positive selection, leading to rapid sequence evolution in other protein domains. In order to characterize the molecular evolution of the human NHEJ pathway, we generated large simian primate sequence datasets for NHEJ genes. Codon-based models of gene evolution yielded statistical support for the recurrent positive selection of five NHEJ genes during primate evolution: XRCC4, NBS1, Artemis, POLλ, and CtIP. Analysis of human polymorphism data using the composite of multiple signals (CMS) test revealed that XRCC4 has also been subjected to positive selection in modern humans. Crystal structures are available for XRCC4, Nbs1, and Polλ; and residues under positive selection fall exclusively on the surfaces of these proteins. Despite the positive selection of such residues, biochemical experiments with variants of one positively selected site in Nbs1 confirm that functions necessary for DNA repair and checkpoint signaling have been conserved. However, many viruses interact with the proteins of the NHEJ pathway as part of their infectious lifecycle. We propose that an ongoing evolutionary arms race between viruses and NHEJ genes may be driving the surprisingly rapid evolution of these critical genes

Organotypic modelling as a means of investigating epithelial-stromal interactions during tumourigenesis

The advent of co-culture approaches has allowed researchers to more accurately model the behaviour of epithelial cells in cell culture studies. The initial work on epidermal modelling allowed the development of reconstituted epidermis, growing keratinocytes on top of fibroblasts seeded in a collagen gel at an air-liquid interface to generate terminally differentiated 'skin equivalents'. In addition to developing ex vivo skin sheets for the treatment of burns victims, such cultures have also been used as a means of investigating both the development and repair of the epidermis, in more relevant conditions than simple two-dimensional culture, but without the use of animals. More recently, by varying the cell types used and adjusting the composition of the matrix components, this physiological system can be adapted to allow the study of interactions between tumour cells and their surrounding stroma, particularly with regards to how such interactions regulate invasion. Here we provide a summary of the major themes involved in tumour progression and consider the evolution of the approaches used to study cancer cell behaviour. Finally, we review how organotypic models have facilitated the study of several key pathways in cancer development and invasion, and speculate on the exciting future roles for these models in cancer research

The Secret Life of the Anthrax Agent Bacillus anthracis: Bacteriophage-Mediated Ecological Adaptations

Ecological and genetic factors that govern the occurrence and persistence of anthrax reservoirs in the environment are obscure. A central tenet, based on limited and often conflicting studies, has long held that growing or vegetative forms of Bacillus anthracis survive poorly outside the mammalian host and must sporulate to survive in the environment. Here, we present evidence of a more dynamic lifecycle, whereby interactions with bacterial viruses, or bacteriophages, elicit phenotypic alterations in B. anthracis and the emergence of infected derivatives, or lysogens, with dramatically altered survival capabilities. Using both laboratory and environmental B. anthracis strains, we show that lysogeny can block or promote sporulation depending on the phage, induce exopolysaccharide expression and biofilm formation, and enable the long-term colonization of both an artificial soil environment and the intestinal tract of the invertebrate redworm, Eisenia fetida. All of the B. anthracis lysogens existed in a pseudolysogenic-like state in both the soil and worm gut, shedding phages that could in turn infect non-lysogenic B. anthracis recipients and confer survival phenotypes in those environments. Finally, the mechanism behind several phenotypic changes was found to require phage-encoded bacterial sigma factors and the expression of at least one host-encoded protein predicted to be involved in the colonization of invertebrate intestines. The results here demonstrate that during its environmental phase, bacteriophages provide B. anthracis with alternatives to sporulation that involve the activation of soil-survival and endosymbiotic capabilities

Viral ecogenomics across the Porifera

BackgroundViruses directly affect the most important biological processes in the ocean via their regulation of prokaryotic and eukaryotic populations. Marine sponges form stable symbiotic partnerships with a wide diversity of microorganisms and this high symbiont complexity makes them an ideal model for studying viral ecology. Here, we used morphological and molecular approaches to illuminate the diversity and function of viruses inhabiting nine sponge species from the Great Barrier Reef and seven from the Red Sea.ResultsViromic sequencing revealed host-specific and site-specific patterns in the viral assemblages, with all sponge species dominated by the bacteriophage order Caudovirales but also containing variable representation from the nucleocytoplasmic large DNA virus families Mimiviridae, Marseilleviridae, Phycodnaviridae, Ascoviridae, Iridoviridae, Asfarviridae and Poxviridae. Whilst core viral functions related to replication, infection and structure were largely consistent across the sponge viromes, functional profiles varied significantly between species and sites largely due to differential representation of putative auxiliary metabolic genes (AMGs) and accessory genes, including those associated with herbicide resistance, heavy metal resistance and nylon degradation. Furthermore, putative AMGs varied with the composition and abundance of the sponge-associated microbiome. For instance, genes associated with antimicrobial activity were enriched in low microbial abundance sponges, genes associated with nitrogen metabolism were enriched in high microbial abundance sponges and genes related to cellulose biosynthesis were enriched in species that host photosynthetic symbionts.ConclusionsOur results highlight the diverse functional roles that viruses can play in marine sponges and are consistent with our current understanding of sponge ecology. Differential representation of putative viral AMGs and accessory genes across sponge species illustrate the diverse suite of beneficial roles viruses can play in the functional ecology of these complex reef holobionts

Spotlight on atezolizumab and its potential in the treatment of advanced urothelial bladder cancer

Ahmet Murat Aydin,1,* Solomon L Woldu,1,* Ryan C Hutchinson,1 Martin Boegemann,2 Aditya Bagrodia,1 Yair Lotan,1 Vitaly Margulis,1 Laura-Maria Krabbe1,2 1Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 2Department of Urology, University of M&uuml;nster Medical Center, M&uuml;nster, Germany *These authors contributed equally to&nbsp;this work Abstract: Metastatic urothelial carcinoma of the bladder is an aggressive malignancy with poor prognosis, reflecting a lack of effective systemic therapies. The current standard of care includes multiagent platinum-based chemotherapy; however a majority of patients do not respond to treatment and most eventually succumb to disease. Recently, renewed interest in immunotherapy in the form of immune-checkpoint inhibition has gained widespread attention for a number of malignancies. Atezolizumab, an anti-PDL1 antibody, has been shown to be effective in a subset of patients previously treated with or unfit for platinum-based chemotherapy, and has shown durable responses with a good tolerability profile. We review the mechanism of action and clinical evidence of atezolizumab for metastatic urothelial bladder cancer, and discuss this drug within the context of ongoing developments in this dynamic field of immunooncology. Keywords: atezolizumab, MPDL3280A, bladder cancer, PDL1, immunotherapy, metastati