Critical Survival Factor Research Articles

Angiopoietin-1 Modified Human Umbilical Cord Mesenchymal Stem Cell Therapy for Endotoxin-Induced Acute Lung Injury in Rats.

PurposeAngiopoietin-1 (Ang1) is a critical factor for vascular stabilization and endothelial survival via inhibition of endothelial permeability and leukocyte- endothelium interactions. Hence, we hypothesized that treatment with umbilical cord mesenchymal stem cells (UCMSCs) carrying the Ang1 gene (UCMSCs-Ang1) might be a potential approach for acute lung injury (ALI) induced by lipopolysaccharide (LPS).Materials and MethodsUCMSCs with or without transfection with the human Ang1 gene were delivered intravenously into rats one hour after intra-abdominal instillation of LPS to induce ALI. After the rats were sacrificed at 6 hours, 24 hours, 48 hours, 8 days, and 15 days post-injection of LPS, the serum, the lung tissues, and bronchoalveolar lavage fluid (BALF) were harvested for analysis, respectively.ResultsAdministration of fluorescence microscope confirmed the increased presence of UCMSCs in the injured lungs. The evaluation of UCMSCs and UCMSCs-Ang1 actions revealed that Ang1 overexpression further decreased the levels of the pro-inflammatory cytokines TNF-α, TGF-β1, and IL-6 and increased the expression of the anti-inflammatory cytokine IL-10 in the injured lungs. This synergy caused a substantial decrease in lung airspace inflammation and vascular leakage, characterized by significant reductions in wet/dry ratio, differential neutrophil counts, myeloperoxidase activity, and BALF. The rats treated by UCMSCs-Ang1 showed improved survival and lower ALI scores.ConclusionUCMSCs-Ang1 could improve both systemic inflammation and alveolar permeability in ALI. UC-derived MSCs-based Ang1 gene therapy may be developed as a potential novel strategy for the treatment of ALI.

Synergistic targeting of Sp1, a critical transcription factor for myeloma cell growth and survival, by panobinostat and proteasome inhibitors.

Panobinostat, a pan-deacetylase inhibitor, synergistically elicits cytotoxic activity against myeloma (MM) cells in combination with the proteasome inhibitor bortezomib. Because precise mechanisms for panobinostat's anti-MM action still remain elusive, we aimed to clarify the mechanisms of anti-MM effects of panobinostat and its synergism with proteasome inhibitors. Although the transcription factor Sp1 was overexpressed in MM cells, the Sp1 inhibitor terameprocol induced MM cell death in parallel with reduction of IRF4 and cMyc. Panobinostat induced activation of caspase-8, which was inversely correlated with reduction of Sp1 protein levels in MM cells. The panobinostat-mediated effects were further potentiated to effectively induce MM cell death in combination with bortezomib or carfilzomib even at suboptimal concentrations as a single agent. Addition of the caspase-8 inhibitor z-IETD-FMK abolished the Sp1 reduction not only by panobinostat alone but also by its combination with bortezomib, suggesting caspase-8-mediated Sp1 degradation. The synergistic Sp1 reduction markedly suppressed Sp1-driven prosurvival factors, IRF4 and cMyc. Besides, the combinatory treatment reduced HDAC1, another Sp1 target, in MM cells, which may potentiate HDAC inhibition. Collectively, caspase-8-mediated post-translational Sp1 degradation appears to be among major mechanisms for synergistic anti-MM effects of panobinostat and proteasome inhibitors in combination.

Tyrosyl-DNA Phosphodiesterase I a critical survival factor for neuronal development and homeostasis.

Tyrosyl-DNA phosphodiesterase I (TDP1), like most DNA repair associated proteins, is not essential for cell viability. However, dysfunctioning TDP1 or ATM (ataxia telangiectasia mutated) results in autosomal recessive neuropathology with similar phenotypes, including cerebellar atrophy. Dual inactivation of TDP1 and ATM causes synthetic lethality. A TDP1H493R catalytic mutant is associated with spinocerebellar ataxia with axonal neuropathy (SCAN1), and stabilizes the TDP1 catalytic obligatory enzyme-DNA covalent complex. The ATM kinase activates proteins early on in response to DNA damage. Tdp1-/- and Atm-/- mice exhibit accumulation of DNA topoisomerase I-DNA covalent complexes (TOPO1-cc) explicitly in neuronal tissue during development. TDP1 resolves 3'- and 5'-DNA adducts including trapped TOPO1-cc and TOPO1 protease resistant peptide-DNA complex. ATM appears to regulate the response to TOPO1-cc via a noncanonical function by regulating SUMO/ubiquitin-mediated TOPO1 degradation. In conclusion, TDP1 and ATM are critical factors for neuronal cell viability via two independent but cooperative pathways.

SME Customer Service Excellence: A Singaporean Case Study

Abstract In Singapore, service sectors are dominated by SMEs. This study set out to investigate customer satisfaction as a critical factor in SME survival and indeed in helping to maintain the overall health of the economy. In this study, data were collected from a Singaporean SME which supplies and installs glass for construction projects. Departments involved were Sales & Marketing, Administration, and Installation. A questionnaire survey was administered to every customer of the company in 2013 in order to evaluate the services provided by the three departments. Customers were categorized into five groups: main contractors, designers/sub-contractors, property managers, home owners and commercial owners. Data were analyzed in terms of thirteen customer service variables identified from the literature. Statistical methods were applied to data analysis and findings were arrived at. Findings were found to be sufficiently significant to permit the formulation of a Total Customer Service Excellence Model for SMEs in Singapore.

Multidrug Resistance-associated Protein-1 (MRP-1)-dependent Glutathione Disulfide (GSSG) Efflux as a Critical Survival Factor for Oxidant-enriched Tumorigenic Endothelial Cells

Endothelial cell tumors are the most common soft tissue tumors in infants. Tumor-forming endothelial (EOMA) cells are able to escape cell death fate despite excessive nuclear oxidant burden. Our previous work recognized perinuclear Nox-4 as a key contributor to EOMA growth. The objective of this work was to characterize the mechanisms by which EOMA cells evade oxidant toxicity and thrive. In EOMA cells, compared with in the cytosol, the nuclear GSSG/GSH ratio was 5-fold higher. Compared to the ratio observed in healthy murine aortic endothelial (MAE) cells, GSSG/GSH was over twice as high in EOMA cells. Multidrug resistance-associated protein-1 (MRP-1), an active GSSG efflux mechanism, showed 2-fold increased activity in EOMA compared with MAE cells. Hyperactive YB-1 and Ape/Ref-1 were responsible for high MRP-1 expression in EOMA. Proximity ligand assay demonstrated MRP-1 and YB-1 binding. Such binding enabled the nuclear targeting of MRP-1 in EOMA in a leptomycin-B-sensitive manner. MRP-1 inhibition as well as knockdown trapped nuclear GSSG, causing cell death of EOMA. Disulfide loading of cells by inhibition of GSSG reductase (bischoloronitrosourea) or thioredoxin reductase (auranofin) was effective in causing EOMA death as well. In sum, EOMA cells survive a heavy oxidant burden by rapid efflux of GSSG, which is lethal if trapped within the cell. A hyperactive MRP-1 system for GSSG efflux acts as a critical survival factor for these cells, making it a potential target for EOMA therapeutics.

Cystatin F Ensures Eosinophil Survival by Regulating Granule Biogenesis

SummaryEosinophils are now recognized as multifunctional leukocytes that provide critical homeostatic signals to maintain other immune cells and aid tissue repair. Paradoxically, eosinophils also express an armory of granule-localized toxins and hydrolases believed to contribute to pathology in inflammatory disease. How eosinophils deliver their supporting functions while avoiding self-inflicted injury is poorly understood. We have demonstrated that cystatin F (CF) is a critical survival factor for eosinophils. Eosinophils from CF null mice had reduced lifespan, reduced granularity, and disturbed granule morphology. In vitro, cysteine protease inhibitors restored granularity, demonstrating that control of cysteine protease activity by CF is critical for normal eosinophil development. CF null mice showed reduced pulmonary pathology in a model of allergic lung inflammation but also reduced ability to combat infection by the nematode Brugia malayi. These data identify CF as a “cytoprotectant” that promotes eosinophil survival and function by ensuring granule integrity.Video

Utilizing IT to Enhance Knowledge Sharing for School Educators in Developing Countries

AbstractKnowledge has been considered a critical factor for any organization's survival however its retention and utilization has remained a challenge to many organizations in developing countries education institutions inclusive. These challenges are mostly attributed to the fact that knowledgeable employees often leave organizations before they could share their valuable knowledge and expertise. In schools of developing countries in particular, educators struggle for subsistence and many leave to seek for greener pastures. Such exodus of educators has led to knowledge loss and has widened the knowledge gap between the schools for the rich and those for the poor. This has been worse especially in the most challenging subjects like Science and Mathematics. Closing this gap, schools need to depend on the knowledge of other experienced educators that are still in the Education system in order to enhance the capabilities of those that are inexperienced. For this reason, leveraging Information Technology (IT) to facilitate the sharing of knowledge, communicate ideas, exchange views and information between educators is paramount. There is a need for schools in developing countries’ to have guidelines of how IT could be utilized for knowledge sharing. The major objective of this paper is therefore to report on the utilization of IT to enhance Knowledge Sharing (KS) among educators in developing countries taking a case of South Africa. The Social Exchange Theory (SET), Theory of Reasoned Action (TRA) and The Unified Theory of Acceptance and Use of Technology (UTAUT) were used to design a conceptual framework for the study. Data was collected from secondary schools’ educators in Tshwane South district of South Africa and was analyzed quantitatively. The results indicated that, knower's attitude is a high significant contributing factor whereas dependence of the knower is the least and insignificant in the utilization of IT to enhance knowledge sharing. Practically, this study could be leveraged by schools and governments to entrench tacit knowledge and to address the brain drainage associated with the continuous exodus of the skilled and experienced educators. Further still, the designed framework could be used by Information Systems scholars to extend research of knowledge sharing and management.

Impact of relapse site on oncological outcomes after radical nephroureterectomy for upper urinary tract urothelial carcinoma.

426 Background: Most upper urinary tract urothelial carcinomas (UTUC) are invasive and advanced with a poor prognosis. Patients often relapse after treatment with radical nephroureterectomy (RNU). However, little is known about an association between sites of recurrence after RNU and oncological outcomes. The present study retrospectively evaluated the impact of a first recurrence site on survival. Methods: A total of 650 patients with UTUC treated by RNU at 12 institutions that participated in the Tohoku Urological Evidence-Based Medicine Study Group between 2000 and 2011 were initially enrolled. Patients who experienced relapse other than intravesical recurrence after RNU were included in this study. Those who had metastasis at the time of UTUC diagnosis or missing data regarding the time and location of relapse were excluded. Finally, 173 patients were eligible to participate in this study. Survival rates were analyzed using Kaplan-Meier curves and the log-rank test, and factors predicting survival were assessed using multivariate analyses. Results: The median follow-up after relapse was nine months. The cancer-specific survival rates at one and two years after relapse were 49% and 22%, respectively. Cancer in 59 (34%), 32 (18%), 23 (13%), and 94 (53%) patients recurred in the lung, liver, bone and lymph nodes, and 23 (13%) had local recurrence. The one-year cancer-specific survival rates were 44%, 27%, 22% and 52% among patients with metastasis of the lungs, liver, bone and lymph nodes respectively, and 41% among those with local recurrence. The survival rate was worse among 48 patients with metastasis at multiple sites, than in those with metastasis at a single site. Fourteen (8%) patients with a single lymph, lung or local recurrence survived for over three years after a first relapse. Multivariate analyses selected the liver, bone and local recurrence as critical factors for cancer-specific survival. Conclusions: Liver or bone metastasis was a negative prognostic factor for UTUC with relapse after RNU. Information about recurrence sites might be helpful for patient counseling.

Vulnerability to climate change of surface water resources of coastal areas of Sindh, Pakistan

The coastal district Thatta of Sindh Province is the area where availability of freshwater is a critical factor for the human survival and livelihood. As such, there are no perennial surface water resources available in the district except of River Indus and its canal system. In view of the changing climate change scenario of the coastal areas of Sindh, this study was undertaken to determine the availability and quality of surface water available in Thatta district. Results of the present investigation indicate that the water from the canals was not suitable for drinking as per WHO guidelines and National Standards for Drinking Water Quality Pakistan. Agriculture run-off, sewage leaks and metals quite often contaminate the surface water resources. However, users have no method to judge its quality except for the taste. Thus, most of the residents drink polluted water unknowingly, and do not question its quality. Increasing variability in rainfall pattern and reduced flow in the River Indus at downstream aggravates the problem that further reducing water supply available for human use.

Downregulated AEG-1 together with inhibited PI3K/Akt pathway is associated with reduced viability of motor neurons in an ALS model.

Astrocyte elevated gene-1 (AEG-1) has been reported to regulate the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and is also regulated by it. This study investigated how AEG-1 participates in the survival pathway of motor neurons in amyotrophic lateral sclerosis (ALS). We found reduced levels of AEG-1 in ALS motor neurons, both in vivo and in vitro, compared to wild type controls. Moreover, AEG-1 silencing demonstrated inhibition of the PI3K/Akt pathway and increased cell apoptosis. Additionally, the PI3K/Akt pathway in mSOD1 cells was unresponsive under serum deprivation conditions compared to wtSOD1 cells. These results suggest that AEG-1 deficiency, together with the inhibited PI3K/Akt pathway was associated with decreased viability of ALS motor neurons. However, the mRNA levels of AEG-1 were still lower in mSOD1 cells compared to the control groups, though the signaling pathway was activated by application of a PI3-K activator. This suggests that in ALS motor neurons, some unknown interruption exists in the PI3K/Akt/CREB/AEG-1 feedback loop, thus attenuating the protection by this signaling pathway. Together, these findings support that AEG-1 is a critical factor for cell survival, and the disrupted PI3K/Akt/CREB/AEG-1cycle is involved in the death of injured motor neurons and pathogenesis of ALS.

Role of the DNA Sensor STING in Protection from Lethal Infection following Corneal and Intracerebral Challenge with Herpes Simplex Virus 1.

STING is a protein in the cytosolic DNA and cyclic dinucleotide sensor pathway that is critical for the initiation of innate responses to infection by various pathogens. Consistent with this, herpes simplex virus 1 (HSV-1) causes invariable and rapid lethality in STING-deficient (STING(-/-)) mice following intravenous (i.v.) infection. In this study, using real-time bioluminescence imaging and virological assays, as expected, we demonstrated that STING(-/-) mice support greater replication and spread in ocular tissues and the nervous system. In contrast, they did not succumb to challenge via the corneal route even with high titers of a virus that was routinely lethal to STING(-/-) mice by the i.v. route. Corneally infected STING(-/-) mice also showed increased periocular disease and increased corneal and trigeminal ganglia titers, although there was no difference in brain titers. They also showed elevated expression of tumor necrosis factor alpha (TNF-α) and CXCL9 relative to control mice but surprisingly modest changes in type I interferon expression. Finally, we also showed that HSV strains lacking the ability to counter autophagy and the PKR-driven antiviral state had near-wild-type virulence following intracerebral infection of STING(-/-) mice. Together, these data show that while STING is an important component of host resistance to HSV in the cornea, its previously shown immutable role in mediating host survival by the i.v. route was not recapitulated following a mucosal infection route. Furthermore, our data are consistent with the idea that HSV counters STING-mediated induction of the antiviral state and autophagy response, both of which are critical factors for survival following direct infection of the nervous system. HSV infections represent an incurable source of morbidity and mortality in humans and are especially severe in neonatal and immunocompromised populations. A key step in the development of an immune response is the recognition of microbial components within infected cells. The host protein STING is important in this regard for the recognition of HSV DNA and the subsequent triggering of innate responses. STING was previously shown to be essential for protection against lethal challenge from intravenous HSV-1 infection. In this study, we show that the requirement for STING depends on the infection route. In addition, STING is important for appropriate regulation of the inflammatory response in the cornea, and our data are consistent with the idea that HSV modulates STING activity through inhibition of autophagy. Our results elucidate the importance of STING in host protection from HSV-1 and demonstrate the redundancy of host protective mechanisms, especially following mucosal infection.

Abstract 3658: Structure-guided de novo design of selective Mcl-1 Inhibitors: Synthesis, structural and biochemical characterization

Abstract Myeloid cell leukemia-1 (Mcl-1) is a potent anti-apoptotic protein, member of the prosurvival Bcl-2 family. Amplification of the gene encoding the Mcl-1 protein is a common genetic aberration in human cancer. Overexpression of Mcl-1 is associated with high tumor grade, resistance to chemotherapy and poor prognosis in many types of cancers. Thus Mcl-1 is emerging as a critical survival factor in a broad range of human cancers and represents an attractive molecular target for development of a new class of cancer therapy. There is still need for developing BH3 mimetics that can efficiently and selectively target Mcl-1 protein. Employing de-novo structure-based drug-design, we have designed a new class of potent small-molecule Mcl-1 inhibitors based on the initial lead compound discovered by high-throughput screening. Analyzing the binding model of this compound with Mcl-1 through computational docking supported by HSQC NMR studies, and using the structural information, we have designed and optimized a class of small-molecule inhibitors of Mcl-1 using a 2-(phenylsulfonamido) benzoic acid as a scaffold to reproduce the key interactions with Mcl-1 such as the conserved hydrogen bond between the aspartate in pro-apoptotic proteins and Arg263 in Mcl-1. Several co-crystal structures of this class inhibitors in complex with Mcl-1 have provided a basis for their further optimization which ultimately led to the discovery of ligands with low-nanomolar potency (Ki = 8 nM) and selectivity for Mcl-1. These compounds bind in the canonical BH3 binding groove. Interestingly, depending on the particular substitution pattern in the core scaffold, a “flip’ binding mode was observed where the substituents bind in a reverse orientation. These findings were confirmed by X-ray crystallography. The most potent compounds were further biologically characterized with a series of complementary biochemical and functional assays. Citation Format: Ahmed Mady, Lei Miao, Andrej Perdih, Chenzhong Liao, Naval Bajwa, Jeanne Stuckey, Zaneta Nikolovska-Coleska. Structure-guided de novo design of selective Mcl-1 Inhibitors: Synthesis, structural and biochemical characterization. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3658. doi:10.1158/1538-7445.AM2015-3658

Genomic analysis and selective small molecule inhibition identifies BCL-X(L) as a critical survival factor in a subset of colorectal cancer.

BackgroundDefects in programmed cell death, or apoptosis, are a hallmark of cancer. The anti-apoptotic B-cell lymphoma 2 (BCL-2) family proteins, including BCL-2, BCL-XL, and MCL-1 have been characterized as key survival factors in multiple cancer types. Because cancer types with BCL2 and MCL1 amplification are more prone to inhibition of their respectively encoded proteins, we hypothesized that cancers with a significant frequency of BCL2L1 amplification would have greater dependency on BCL-XL for survival.MethodsTo identify tumor subtypes that have significant frequency of BCL2L1 amplification, we performed data mining using The Cancer Genome Atlas (TCGA) database. We then assessed the dependency on BCL-XL in a panel of cell lines using a selective and potent BCL-XL inhibitor, A-1155463, and BCL2L1 siRNA. Mechanistic studies on the role of BCL-XL were further undertaken via a variety of genetic manipulations.ResultsWe identified colorectal cancer as having the highest frequency of BCL2L1 amplification across all tumor types examined. Colorectal cancer cell lines with BCL2L1 copy number >3 were more sensitive to A-1155463. Consistently, cell lines with high expression of BCL-XL and NOXA, a pro-apoptotic protein that antagonizes MCL-1 activity were sensitive to A-1155463. Silencing the expression of BCL-XL via siRNA killed the cell lines that were sensitive to A-1155463 while having little effect on lines that were resistant. Furthermore, silencing the expression of MCL-1 in resistant cell lines conferred sensitivity to A-1155463, whereas silencing NOXA abrogated sensitivity.ConclusionsThis work demonstrates the utility of characterizing frequent genomic alterations to identify cancer survival genes. In addition, these studies demonstrate the utility of the highly potent and selective compound A-1155463 for investigating the role of BCL-XL in mediating the survival of specific tumor types, and indicate that BCL-XL inhibition could be an effective treatment for colorectal tumors with high BCL-XL and NOXA expression.

Phage-AgNPs complex as SERS probe for U937 cell identification.

The early diagnosis of malignancy is the most critical factor for patient survival and the treatment of cancer. In particular, leukemic cells are highly heterogeneous, and there is a need to develop new rapid and accurate detection systems for early diagnosis and monitoring of minimal residual disease. This study reports the utilization of molecular networks consisting of entire bacteriophage structure, displaying specific peptides, directly assembled with silver nanoparticles as a new Surface Enhanced Raman Spectroscopy (SERS) probe for U937 cells identification in vitro. A 9-mer pVIII M13 phage display library is screened against U937 to identify peptides that selectively recognize these cells. Then, phage clone is assembled with silver nanoparticles and the resulting network is used to obtain a SERS signal on cell-type specific molecular targets. The proposed strategy could be a very sensitive tool for the design of biosensors for highly specific and selective identification of hematological cancer cells and for detection of minimal residual disease in a significant proportion of human blood malignancy.

Marginal quality and wear of extended posterior resin composite restorations: Eight-year results in vivo

AimTo evaluate wear and marginal quality of resin composite restorations over eight years of clinical service in vivo. Methods30 patients received 68 resin composite restorations (36 Grandio, 32 Tetric Ceram) in the course of a prospective clinical trial. 3-D evaluation of 36 selected teeth involving 144 epoxy replicas was carried out using a special 3-D scanning device with an accuracy of U1=2.5+L/350μm; U3=3+L/300μm. In vivo replicas were sputter-coated with gold and examined under a SEM at 200× magnification. Marginal integrity between resin composite and enamel was expressed as a percentage of the entire judgeable margin length. ResultsDuring the clinical 8-year observation period, wear significantly increased in the restored areas as well as in OCAs. RBCs under investigation showed no significant differences regarding wear (p>0.05). Localization of the restorations (premolar vs. molar or upper vs. lower) did not show a significant influence on wear rates (p>0.05). Clinically, by SEM, and by 3-D scanning distinct changes of worn contours on enamel and RBC were visible. Quantitative margin analysis revealed a change of perfect margins (58% at baseline vs. 14% at 8 years), positive step formations (15% at baseline vs. 10% at 8 years), and negative step formations (20% at baseline vs. 71% at 8 years) over time (p<0.001). Regarding the portion of gap-free margins (baseline vs. 2 years) and total margin length (baseline to 8 years), Grandio showed lower values (Mann-Whitney U-test; p<0.05). The portion of negative step formations was lower for Tetric Ceram at baseline (Mann-Whitney-U test; p<0.05). ConclusionsAfter eight years of clinical service, neither wear nor marginal quality was a critical factor for estimation and survival of extended posterior resin composite restorations.

Overexpression of pyruvate kinase M2 associates with aggressive clinicopathological features and unfavorable prognosis in oral squamous cell carcinoma

Abnormal glucose metabolism mediated by pyruvate kinase M2 (PKM2) fuels cancer overgrowth and propagation. However, its expression and oncogenic roles in in oral squamous cell carcinoma (OSCC) remains incompletely known. Here, we aimed to investigate the expression of PKM2, its prognostic values and oncogenic functions using 7,12-dimethyl-1,2-bezan-tracene (DMBA)-induced hamster buccal pouch SCC model, primary OSCC specimens as well as in vitro cellular assays. We found that in DMBA-induced OSCC model, negative PKM2 expression was commonly observed in normal epithelial, while more PKM2 abundance was detected in hyperplasia, dysplasia and SCC. Overexpression of PKM2 in a major fraction of OSCC significantly associated with tumor size (P = 0.027), cervical node metastasis (P = 0.004) and clinical stages (P = 0.000). Patients with increased PKM2 had remarkably reduced overall and disease-free survival. Multivariate survival analysis further revealed that PKM served as a critical independent prognostic factor for patients' overall survival. Furthermore, impaired cell proliferation and migration, and reduced apoptosis were detected upon PKM2 knockdown in HN4 and HN12 cells. Taken together, our findings reveal that PKM2 is critically involved in OSCC initiation and progression probably by promoting cell proliferation and migration as well as reducing apoptosis. Its overexpression correlates with aggressive clinicopathological features and poor patients' outcome.

Upper thermal tolerance in anuran embryos and tadpoles at constant and variable peak temperatures

Anuran survival is strongly affected by exposure to high environmental temperatures. However, their upper thermal tolerances vary between species and within developmental stages. The aims of this research were to measure the median lethal temperature (LT50) of three anuran developmental stages (Gosner stages 10, 20, and 25) at a constant thermal regime, and of developing embryos (stage 10) until they became tadpoles (stage 25) exposed to daily peaks of temperatures between 1000 and 1600. Four Colombian species (Emerald-eyed Treefrog, Hypsiboas crepitans (Wied-Neuwied, 1824); Tungara Frog, Engystomops pustulosus (Cope, 1864); Rivero’s Toad, Rhinella humboldti (Gallardo, 1965); Emerald Glassfrog, Espadarana prosoblepon (Boettger, 1892)) were used in these experiments. An ontogenetic increase was observed in the upper thermal tolerance from embryos to tadpoles for all species studied. In addition, developing embryos exposed to peak temperatures showed a LT50fairly close to the mean of the maximum habitat temperatures, particularly in H. crepitans and E. pustulosus that lay egg masses exposed directly to the sun. Environmental temperatures in the microhabitat of species studied showed values remarkably higher than their experimental LT50. Therefore, we postulate that rapid increases in environmental temperatures, as result of global or local changes, might be a critical factor for anuran survival, mainly during the embryonic stages when they are more sensitive to temperature.

Influence of wind, wave, and water level dynamics on walleye eggs in a north temperate lake

Walleye (Sander vitreus) populations are cyclic because of biotic and abiotic factors, and wind activity, wave energy, and water levels may be influential given walleye spawn close to shore. We installed an anemometer and tridirectional velocimeter on a spawning reef in Big Crooked Lake, Wisconsin, in 2005 to determine wind–wave relationships and wave energy exceedance of critical velocities of both egg (affecting transport) and substrates (affecting abrasion or burial). To evaluate egg movement, we delineated egg locations at adhesive, postspawn, and black-eyed stages and surveyed on-shore for stranded eggs. We monitored water level with a staff gauge. Wind and wave velocities were significantly (p &lt; 0.01) correlated, and wave velocities were significantly higher (p &lt; 0.01) nearshore (2.0 m) than further from shore (4.6 m). Mean nearshore wave velocities were often sufficient to initiate movement of nonadhesive eggs (45% of records) and fine sand (39%) during egg incubation. Surveys indicated waves moved eggs closer to shore and some onto shore. Water level fluctuations (range = 2.4 cm) likely did not strand or desiccate eggs. We documented that wind and wave activity transports eggs and substrates and should be considered a critical factor in annual walleye egg survival and year-class strength.

The role of CD95 and CD95 ligand in cancer.

CD95 (Fas/APO-1) and its ligand, CD95L, have long been viewed as a death receptor/death ligand system that mediates apoptosis induction to maintain immune homeostasis. In addition, these molecules are important in the immune elimination of virus-infected cells and cancer cells. CD95L was, therefore, considered to be useful for cancer therapy. However, major side effects have precluded its systemic use. During the last 10 years, it has been recognized that CD95 and CD95L have multiple cancer-relevant nonapoptotic and tumor-promoting activities. CD95 and CD95L were discovered to be critical survival factors for cancer cells, and were found to protect and promote cancer stem cells. We now discuss five different ways in which inhibiting or eliminating CD95L, rather than augmenting, may be beneficial for cancer therapy alone or in combination with standard chemotherapy or immune therapy.

Clinical characteristics of the mixed form of neuroendocrine tumor in the lung: A retrospective study in 2501 lung cancer cases.

BackgroundA neuroendocrine tumor (NET) is a special kind of epithelial tumor with predominant neuroendocrine differentiation, which arises throughout the body, including the lung. A subpopulation of lung cancer patients suffer from the mixed (combined) form of NET with components of non-neuroendocrine carcinoma. However, the clinical characteristics of the mixed form of NET are not well established.MethodsWe analyzed 2501 consecutive cases of primary lung cancer from 2009 to 2011. The diagnosis, histology, therapy, and outcome were collected.ResultsA total of 22 patients were enrolled. The occurrence rate of lung cancer was 0.9%. Neither gender (1.2% and 0.3% for male and female, respectively, P = 0.35) nor age (0.6% and 1.3% for patients aged ≤60 and >60, respectively, P = 0.13) was associated with the onset of this disease; however it has become more frequent in recent years (0.6% and 1.6% at the time ≤ and >2010 respectively, P = 0.03). This cohort of 22 patients had a median survival of 60.0 months (95% confidence interval: 14.3–105.6 months). Patients with metastatic disease (60 months and not reached [NR], P = 0.18) or a small-cell lung cancer component tended to have a shorter survival (35 months and NR, P = 0.16). Patients who underwent surgery had a significantly longer survival period (NR and 17.0 months, P = 0.001).ConclusionsA mixed form of NET in the lung is a rare disease. While stage and histology might influence prognosis, surgery is the critical factor for long-term survival.