On the Validity of Using Increases in 5-Year Survival Rates to Measure Success in the Fight against Cancer

Background

The 5-year survival rate of cancer patients is the most commonly used statistic to reflect improvements in the war against cancer. This idea, however, was refuted based on an analysis showing that changes in 5-year survival over time bear no relationship with changes in cancer mortality.

Methods

Here we show that progress in the fight against cancer can be evaluated by analyzing the association between 5-year survival rates and mortality rates normalized by the incidence (mortality over incidence, MOI). Changes in mortality rates are caused by improved clinical management as well as changing incidence rates, and since the latter can mask the effects of the former, it can also mask the correlation between survival and mortality rates. However, MOI is a more robust quantity and reflects improvements in cancer outcomes by overcoming the masking effect of changing incidence rates. Using population-based statistics for the US and the European Nordic countries, we determined the association of changes in 5-year survival rates and MOI.

Results

We observed a strong correlation between changes in 5-year survival rates of cancer patients and changes in the MOI for all the countries tested. This finding demonstrates that there is no reason to assume that the improvements in 5-year survival rates are artificial. We obtained consistent results when examining the subset of cancer types whose incidence did not increase, suggesting that over-diagnosis does not obscure the results.

Conclusions

We have demonstrated, via the negative correlation between changes in 5-year survival rates and changes in MOI, that increases in 5-year survival rates reflect real improvements over time made in the clinical management of cancer. Furthermore, we found that increases in 5-year survival rates are not predominantly artificial byproducts of lead-time bias, as implied in the literature. The survival measure alone can therefore be used for a rough approximation of the amount of progress in the clinical management of cancer, but should ideally be used with other measures.     

Novel Small Molecule XPO1/CRM1 Inhibitors Induce Nuclear Accumulation of TP53, Phosphorylated MAPK and Apoptosis in Human Melanoma Cells

XPO1/CRM1 is a key nuclear exporter protein that mediates translocation of numerous cellular regulatory proteins. We investigated whether XPO1 is a potential therapeutic target in melanoma using novel selective inhibitors of nuclear export (SINE). In vitro effects of SINE on cell growth and apoptosis were measured by MTS assay and flow cytometry [Annexin V/propidium iodide (PI)], respectively in human metastatic melanoma cell lines. Immunoblot analysis was used to measure nuclear localization of key cellular proteins. The in vivo activity of oral SINE was evaluated in NOD/SCID mice bearing A375 or CHL-1 human melanoma xenografts. SINE compounds induced cytostatic and pro-apoptotic effects in both BRAF wild type and mutant (V600E) cell lines at nanomolar concentrations. The cytostatic and pro-apoptotic effects of XPO1 inhibition were associated with nuclear accumulation of TP53, and CDKN1A induction in the A375 cell line with wild type TP53, while pMAPK accumulated in the nucleus regardless of TP53 status. The orally bioavailable KPT-276 and KPT-330 compounds significantly inhibited growth of A375 (p<0.0001) and CHL-1 (p = 0.0087) human melanoma cell lines in vivo at well tolerated doses. Inhibition of XPO1 using SINE represents a potential therapeutic approach for melanoma across cells with diverse molecular phenotypes by promoting growth inhibition and apoptosis.     

ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage

ATM is one of the sentries at the gate of genome stability. This multifunctional protein kinase orchestrates the intricate array of cellular responses to DNA double-strand breaks. Absence or inactivation of ATM leads to the pleiotropic genetic disorder ataxia-telangiectasia (A-T), whose hallmarks are neuronal degeneration, immunodeficiency, genomic instability, premature aging and cancer predisposition. Several features of the complex clinical and cellular phenotype of A-T are reminiscent of other syndromes involving neurodegeneration, premature aging or genomic instability. A common denominator of many of these conditions is the perturbation of the cellular balance of reactive oxygen species, which leads to constant oxidative stress. Of these disorders, ATM deficiency is one of the most extensively studied with regard to the genome instability-oxidative stress connection. This connection may provide new insights into the phenotypes associated with genetic deficiencies of DNA damage responses, and point to new strategies to alleviate some of their clinical symptoms.     

Systematic identification of gene annotation errors in the widely used yeast mutation collections

The baker's yeast mutation collections are extensively used genetic resources that are the basis for many genome-wide screens and new technologies. Anecdotal evidence has previously pointed to the putative existence of a neighboring gene effect (NGE) in these collections. NGE occurs when the phenotype of a strain carrying a particular perturbed gene is due to the lack of proper function of its adjacent gene. Here we performed a large-scale study of NGEs, presenting a network-based algorithm for detecting NGEs and validating software predictions using complementation experiments. We applied our approach to four datasets uncovering a similar magnitude of NGE in each (7-15%). These results have important consequences for systems biology, as the mutation collections are extensively used in almost every aspect of the field, from genetic network analysis to functional gene annotation.     

The earliest matches

Cylindrical objects made usually of fired clay but sometimes of stone were found at the Yarmukian Pottery Neolithic sites of Sha'ar HaGolan and Munhata (first half of the 8(th) millennium BP) in the Jordan Valley. Similar objects have been reported from other Near Eastern Pottery Neolithic sites. Most scholars have interpreted them as cultic objects in the shape of phalli, while others have referred to them in more general terms as "clay pestles," "clay rods," and "cylindrical clay objects." Re-examination of these artifacts leads us to present a new interpretation of their function and to suggest a reconstruction of their technology and mode of use. We suggest that these objects were components of fire drills and consider them the earliest evidence of a complex technology of fire ignition, which incorporates the cylindrical objects in the role of matches.     

Ce-emerin and LEM-2: essential roles in Caenorhabditis elegans development, muscle function, and mitosis

Emerin and LEM2 are ubiquitous inner nuclear membrane proteins conserved from humans to Caenorhabditis elegans. Loss of human emerin causes Emery-Dreifuss muscular dystrophy (EDMD). To test the roles of emerin and LEM2 in somatic cells, we used null alleles of both genes to generate C. elegans animals that were either hypomorphic (LEM-2-null and heterozygous for Ce-emerin) or null for both proteins. Single-null and hypomorphic animals were viable and fertile. Double-null animals used the maternal pool of Ce-emerin to develop to the larval L2 stage, then arrested. Nondividing somatic cell nuclei appeared normal, whereas dividing cells had abnormal nuclear envelope and chromatin organization and severe defects in postembryonic cell divisions, including the mesodermal lineage. Life span was unaffected by loss of Ce-emerin alone but was significantly reduced in LEM-2-null animals, and double-null animals had an even shorter life span. In addition to striated muscle defects, double-null animals and LEM-2-null animals showed unexpected defects in smooth muscle activity. These findings implicate human LEM2 mutations as a potential cause of EDMD and further suggest human LEM2 mutations might cause distinct disorders of greater severity, since C. elegans lacking only LEM-2 had significantly reduced life span and smooth muscle activity.     

An annotated checklist of the horse flies (Diptera: Tabanidae) of Lebanon with remarks on ecology and zoogeography: Pangoniinae and Chrysopsinae

Knowledge of the horse fly fauna (Diptera: Tabanidae) of Lebanon is fragmentary, while the local fauna of most neighboring countries has been fairly well researched. Within the framework of the 20-year project "The ecology and zoogeography of the Lepidoptera of the Near East," we regularly collected biting flies in the whole region, including Lebanon. During this time we recorded 14 horse fly species for two subfamilies in Lebanon: four Pangoniinae and ten Chrysopsinae. Only a single species, Chrysops flavipes Meigen, 1804, was known previously in Lebanon, but the following four Pangoniinae: Pangonius haustellatus (Fabricius, 1781), Pangonius obscuratus Loew, 1859, Pangonius argentatus (Szilady, 1923), and Pangonius fulvipes (Loew, 1859) and nine Chrysopsinae: Silvius appendiculatus Macquart, 1846, Silvius ochraceus Loew, 1858, Nemorius irritans (Ricardo, 1901), Nemorius vitripennis (Meigen, 1820), Chrysops buxtoniAusten, 1922, Chrysops compactusAusten, 1924, Chrysops caecutiens (Linnaeus, 1758), Chrysops italicus Meigen, 1804, and Chrysops hamatus Loew, 1858 are new records for the Lebanese fauna. The Tabanidae fauna of Lebanon is completely Palearctic and most species are of a Mediterranean distribution type. Lebanon or nearby northern Israel appears to be in the Levant, the southern geographical distribution border for the Pangoniinae and Chrysopsinae.     

雄性弯角长角羚和普通大羚羊激素分泌模式与社会等级和季节的关系

为了确定羚羊类固醇激素分泌模式与行为和社群等级的关系,我们检测了成年雄性弯角长角羚(n=15)和普通大羚羊(n=11)的粪样皮质酮和睾酮浓度.采用随意取样和目标取样法记录了共650 h的行为.结果发现,两种羚羊的睾酮水平在雌性的发情时段里都是最高的.两种羚羊皮质激素水平有季节性变化,表现为雨季皮质酮水平高于干旱季节.优势胁迫作用明显存在于普通大羚羊,而在弯角长角羚不明显.没有证据表明从属个体压力的存在,一只弯角长角羚曾经是优势个体,但是后来有两年不是优势个体,与其他雄羚相比,这只雄羚在雌性发情期的睾酮和皮质酮水平有3个交迭出现的峰值.     

Parameters involved in antimicrobial and endotoxin detoxification activities of antimicrobial peptides

Endotoxin [lipopolysaccharide (LPS)] covers more than 90% of the outer monolayer of the outer membrane of Gram-negative bacteria, and it plays a dual role in its pathogenesis: as a protective barrier against antibiotics and as an effector molecule, which is recognized by and activates the innate immune system. The ability of host-defense antimicrobial peptides to bind LPS on intact bacteria and in suspension has been implicated in their antimicrobial and LPS detoxification activities. However, the mechanisms involved and the properties of the peptides that enable them to traverse the LPS barrier or to neutralize LPS endotoxic activity are not yet fully understood. Here we investigated a series of antimicrobial peptides and their analogues with drastically altered sequences and structures, all of which share the same amino acid composition (K 6L 9). The list includes both all- l-amino acid peptides and their diastereomers (composed of both l- and d-amino acids). The peptides were investigated functionally for their antibacterial activity and their ability to block LPS-dependent TNF-alpha secretion by macrophages. Fluorescence spectroscopy and transmission electron microscopy were used to detect their ability to bind LPS and to affect its oligomeric state. Their secondary structure was characterized in solution, in LPS suspension, and in LPS multibilayers by using CD and FTIR spectroscopy. Our data reveal specific biophysical properties of the peptides that are required to kill bacteria and/or to detoxify LPS. Besides shedding light on the mechanisms of these two important functions, the information gathered should assist in the development of AMPs with potent antimicrobial and LPS detoxification activities.