Oral cancer cells may rewire alternative metabolic pathways to survive from siRNA silencing of metabolic enzymes.

BackgroundCancer cells may undergo metabolic adaptations that support their growth as well as drug resistance properties. The purpose of this study is to test if oral cancer cells can overcome the metabolic defects introduced by using small interfering RNA (siRNA) to knock down their expression of important metabolic enzymes.MethodsUM1 and UM2 oral cancer cells were transfected with siRNA to transketolase (TKT) or siRNA to adenylate kinase (AK2), and Western blotting was used to confirm the knockdown. Cellular uptake of glucose and glutamine and production of lactate were compared between the cancer cells with either TKT or AK2 knockdown and those transfected with control siRNA. Statistical analysis was performed with student T-test.ResultsDespite the defect in the pentose phosphate pathway caused by siRNA knockdown of TKT, the survived UM1 or UM2 cells utilized more glucose and glutamine and secreted a significantly higher amount of lactate than the cells transferred with control siRNA. We also demonstrated that siRNA knockdown of AK2 constrained the proliferation of UM1 and UM2 cells but similarly led to an increased uptake of glucose/glutamine and production of lactate by the UM1 or UM2 cells survived from siRNA silencing of AK2.ConclusionsOur results indicate that the metabolic defects introduced by siRNA silencing of metabolic enzymes TKT or AK2 may be compensated by alternative feedback metabolic mechanisms, suggesting that cancer cells may overcome single defective pathways through secondary metabolic network adaptations. The highly robust nature of oral cancer cell metabolism implies that a systematic medical approach targeting multiple metabolic pathways may be needed to accomplish the continued improvement of cancer treatment

Investigating variation in replicability

Although replication is a central tenet of science, direct replications are rare in psychology. This research tested variation in the replicability of 13 classic and contemporary effects across 36 independent samples totaling 6,344 participants. In the aggregate, 10 effects replicated consistently. One effect – imagined contact reducing prejudice – showed weak support for replicability. And two effects – flag priming influencing conservatism and currency priming influencing system justification – did not replicate. We compared whether the conditions such as lab versus online or US versus international sample predicted effect magnitudes. By and large they did not. The results of this small sample of effects suggest that replicability is more dependent on the effect itself than on the sample and setting used to investigate the effect

Machine learning uncovers the most robust self-report predictors of relationship quality across 43 longitudinal couples studies

Given the powerful implications of relationship quality for health and well-being, a central mission of relationship science is explaining why some romantic relationships thrive more than others. This large-scale project used machine learning (i.e., Random Forests) to 1) quantify the extent to which relationship quality is predictable and 2) identify which constructs reliably predict relationship quality. Across 43 dyadic longitudinal datasets from 29 laboratories, the top relationship-specific predictors of relationship quality were perceived-partner commitment, appreciation, sexual satisfaction, perceived-partner satisfaction, and conflict. The top individual-difference predictors were life satisfaction, negative affect, depression, attachment avoidance, and attachment anxiety. Overall, relationship-specific variables predicted up to 45% of variance at baseline, and up to 18% of variance at the end of each study. Individual differences also performed well (21% and 12%, respectively). Actor-reported variables (i.e., own relationship-specific and individual-difference variables) predicted two to four times more variance than partner-reported variables (i.e., the partner’s ratings on those variables). Importantly, individual differences and partner reports had no predictive effects beyond actor-reported relationship-specific variables alone. These findings imply that the sum of all individual differences and partner experiences exert their influence on relationship quality via a person’s own relationship-specific experiences, and effects due to moderation by individual differences and moderation by partner-reports may be quite small. Finally, relationship-quality change (i.e., increases or decreases in relationship quality over the course of a study) was largely unpredictable from any combination of self-report variables. This collective effort should guide future models of relationships

The Role of SOX5 in the Progression of Oral Squamous Cell Carcinoma

Background: Cancer of the head and neck, including oral, laryngeal, and pharyngeal sites, is the sixth most common malignancy in the world. Every year, nearly 650,000 patients worldwide receive the diagnosis of head and neck cancer, and around 350,000 die from this disease [1]. More than 95% of these cancers are head and neck squamous cell carcinoma (HNSCC) in histology [1]. Early detection of the cancer and discovery of new targeted therapies are a few of the main approaches that may be able to increase patient survival rates.SOX5, or the SRY box 5 protein, is a member of the SOX family of transcription factors and has yet to be fully characterized in oral cancer. In cancer biology, SOX5 has been shown to be involved in epithelial to mesenchymal transition (EMT) in breast cancer, hepatocellular cancer, prostate cancer, lung adenocarcinoma, and osteosarcoma [2-6]. SOX5 has also recentlybeen linked to nasopharyngeal cancer, but no study to date has described the role of SOX5 in oral cancer [7].Equally significant in the pathogenesis of HNSCC, overexpression of epithelial growth factor (EGF) and its receptor(EGFR) has been found in roughly 90% of HNSCC tumors [8]. The downstream target effectors of EGFR, including the JAK/STAT pathway, have also been shown to be activated in HNSCC [8, 9]. In particular, STAT3 is known to be constitutively activated in many types of cancers, including HNSCC [8, 10].Objectives: This study aims to identify the role and regulating mechanisms of SOX5 in oral cancer. Considering the prominence of EGFR and STAT3 in HNSCC, a link between STAT3 and SOX5 could help to elucidate a pathway of activation and regulation. SOX5 has been shown to be a downstream target of STAT3 in murine Th17 cells, but no relationship has yet been defined in cancer.Methods: Phenotypic studies were conducted in highly invasive oral cancer cell lines (UM1 and UM5) with knockdown of SOX5 and in a low-invasive oral cancer cell line (UM2) with SOX5 upregulation. MTT, migration, and invasion assays were utilized to assess phenotype, and Western blotting and qPCR were used to quantify protein and gene expression levels. Chromatin immunoprecipitation (ChIP) followed by qPCR was used to examine if STAT3 binds to the promoter of SOX5.Results: Endogenous SOX5 is up-regulated in UM1 and UM5 cells, when compared to UM2and UM6 cells, respectively (p<0.05). Knockdown of SOX5 in UM1 and UM5 cells shows decreased proliferation, migration, and invasion potential. When treated with EGF, expression of SOX5 increased in all cell lines, and UM2 showed an increased ability to migrate and invade. ChIPassay results indicate that STAT3 binds to the promoter region of SOX5 in both UM1 and UM5 cells.Conclusions: This study has demonstrated that SOX5 may play an important role in head and neck cancer progression by promoting cancer cell growth, migration, and invasion. EGF induces the expression of SOX5 in head and neck cancer cells via the regulation of STAT3 and enhances cancer cell migration and invasion. These findings suggest that EGF-STAT3-SOX5 axis is an important regulatory pathway in head and neck cancer progression

Biochemical Effects of Lead, Zinc, and Cadmium from Mining on Fish in the Tri-States District of Northeastern Oklahoma, USA

We assessed the exposure of fish from the Spring and Neosho Rivers in northeast Oklahoma, USA, to lead, zinc, and cadmium from historical mining in the Tri-States Mining District (TSMD). Fish (n = 74) representing six species were collected in October 2001 from six sites on the Spring and Neosho Rivers influenced to differing degrees by mining. Additional samples were obtained from the Big River, a heavily contaminated stream in eastern Missouri, USA, and from reference sites. Blood from each fish was analyzed for Pb, Zn, Cd, Fe, and hemoglobin (Hb). Blood also was analyzed for δ-aminolevulinic acid dehydratase (ALA-D) activity. The activity of ALA-D, an enzyme involved in heme synthesis, is inhibited by Pb. Concentrations of Fe and Hb were highly correlated (r = 0.89, p \u3c 0.01) across all species and locations and typically were greater in common carp (Cyprinus carpio) than in other taxa. Concentrations of Pb, Zn, and Cd typically were greatest in fish from sites most heavily affected by mining and lowest in reference samples. The activity of ALA-D, but not concentrations of Hb or Fe, also differed significantly (p \u3c 0.01) among sites and species. Enzyme activity was lowest in fish from mining-contaminated sites and greatest in reference fish, and was correlated negatively with Pb in most species. Statistically significant (p \u3c 0.01) linear regression models that included negative terms for blood Pb explained as much as 68% of the total variation in ALA-D activity, but differences among taxa were highly evident. Positive correlations with Zn were documented in the combined data for channel catfish (Ictalurus punctatus) and flathead catfish (Pylodictis olivaris), as has been reported for other taxa, but not in bass (Micropterus spp.) or carp. In channel catfish, ALA-D activity appeared to be more sensitive to blood Pb than in the other species investigated (i.e., threshold concentrations for inhibition were lower). Such among-species differences are consistent with previous studies. Enzyme activity was inhibited by more than 50% relative to reference sites in channel catfish from several TSMD sites. Collectively, our results indicate that Pb is both bioavailable and active biochemically in the Spring–Neosho River system

Concentrations of elements in hellbender blood and fish fillets from the Missouri Department of Conservation monitoring programs

This report presents the results of contaminant monitoring surveys conducted annually by the Missouri Department of Conservation to examine the levels of selected elemental contaminants in hellbender (Cryptobranchus alleganiensis) blood and fish. Catfish (Ictalurus furcatus, Ictalurus punctatus, Pylodictis olivaris), redhorse (Moxostoma anisorum, Moxostoma erythrurum), bass (Micropterus salmoides, Micropterus punctulatus, Micropterus lacepède, Ambloplites rupestris), walleye (Sander vitreus), and sunfish (Lepomis megalotis) were collected from 17 sites as part of the Department\u27s General Contaminant Monitoring Program. Bluegill (Lepomis macrochirus) and other sunfish (Lepomis megalotis, Lepomis cyanellus) were collected from 18 sites as part of the Department\u27s Resource Assessment and Monitoring Program. Blood from hellbenders was collected from seven sites as part of the Department\u27s Hellbender Monitoring Program

Oral cancer cells may rewire alternative metabolic pathways to survive from siRNA silencing of metabolic enzymes.

BackgroundCancer cells may undergo metabolic adaptations that support their growth as well as drug resistance properties. The purpose of this study is to test if oral cancer cells can overcome the metabolic defects introduced by using small interfering RNA (siRNA) to knock down their expression of important metabolic enzymes.MethodsUM1 and UM2 oral cancer cells were transfected with siRNA to transketolase (TKT) or siRNA to adenylate kinase (AK2), and Western blotting was used to confirm the knockdown. Cellular uptake of glucose and glutamine and production of lactate were compared between the cancer cells with either TKT or AK2 knockdown and those transfected with control siRNA. Statistical analysis was performed with student T-test.ResultsDespite the defect in the pentose phosphate pathway caused by siRNA knockdown of TKT, the survived UM1 or UM2 cells utilized more glucose and glutamine and secreted a significantly higher amount of lactate than the cells transferred with control siRNA. We also demonstrated that siRNA knockdown of AK2 constrained the proliferation of UM1 and UM2 cells but similarly led to an increased uptake of glucose/glutamine and production of lactate by the UM1 or UM2 cells survived from siRNA silencing of AK2.ConclusionsOur results indicate that the metabolic defects introduced by siRNA silencing of metabolic enzymes TKT or AK2 may be compensated by alternative feedback metabolic mechanisms, suggesting that cancer cells may overcome single defective pathways through secondary metabolic network adaptations. The highly robust nature of oral cancer cell metabolism implies that a systematic medical approach targeting multiple metabolic pathways may be needed to accomplish the continued improvement of cancer treatment