Feasibility of Integrating Tripterygium wilfordii into Modern Cancer Therapy for Increased Efficacy with Minimal Toxicity

Cancer is the second leading cause of death in the U.S., and millions of novel cancer cases are being diagnosed each year. While chemotherapy and ionizing radiation are effective treatments against these malignant tumors, the adverse effects that accompany such treatments are devastating. In order to find alternative treatment methods with less side effects, we turn to Eastern herbal medicine. Recent scientific research has found that Tripterygium wilfordii, an herbal medicine traditionally used to treat inflammation in China, contains compounds (triptolide and celastrol) that prevent the growth of solid tumors, induce apoptosis, and prevent metastasis of developed tumors. Investigations on these compounds on various cancer cells lines (in vitro and in vivo) have revealed insight into their mechanism, mode of action, and toxicity. In order to circumvent the potentially fatal side effects of triptolide and celastrol, it was proposed that roots of T. wilfordii, from which the compounds are extracted, be used as a treatment for cancer. Methods for testing the efficacy and toxicity of the roots on the different cell lines previously studied are outlined in this paper. If the results from the proposed experiment conflict with expectation, then future studies on combination drugs using triptolide and celastrol with other non-bioactive compounds within the roots should be done to develop new anti-cancer drugs with low toxicity

Exploring size effects in copper-chromium-zirconium using indentation techniques and in-situ micro-pillar compression

The influence of microstructure on the mechanical properties of materials has been the focus of research over several decades, with various attempts made to characterize this size effect numerically, e.g. the Hall-Petch relationship. This behaviour is overlaid with an extrinsic size dependence that scales with the testing technique used, whereby the smaller the sampled volume the stronger the material appears to behave. Considering the growing trend towards miniaturised mechanical testing, particularly in the electronics industry and nuclear community, both forms of the size effect need to be fully understood in order to achieve engineering-relevant results. In particular, knowing how the two contribute cumulatively in different material systems is non-trivial and requires further investigation. Please click Additional Files below to see the full abstract

Loss of fibrinogen in zebrafish results in an asymptomatic embryonic hemostatic defect and synthetic lethality with thrombocytopenia

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148369/1/jth14391.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148369/2/jth14391-sup-0001-Supinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148369/3/jth14391_am.pd

Can Surgical Trainees Achieve Arthroscopic Competence at the End of Training Programs? A Cross-sectional Study Highlighting the Impact of Working Time Directives.

PURPOSE: To provide training guidance on procedure numbers by assessing how the number of previously performed arthroscopic procedures relate to both competent and expert performance in simulated arthroscopic shoulder tasks. METHODS: A cross-sectional study that assessed simulated shoulder arthroscopic performance was undertaken. A total of 45 participants of varying experience performed 2 validated tasks: a simple diagnostic task and a more complex Bankart labral repair task. All participants provided logbook numbers for previously performed arthroscopies. Performance was assessed with the Global Rating Scale and motion analysis. Receiver operating characteristic curve analyses were conducted to identify optimum cut points for task proficiency at both "competent" and "expert" levels. RESULTS: Increasing surgical experience resulted in significantly better performance for both tasks as assessed by Global Rating Scale or motion analysis (P < .0001). Receiver operating characteristic curve analyses demonstrated 52 previous arthroscopies were needed to perform to a competent level at the diagnostic task and 248 to be competent at the complex task. To perform at an expert level, 290 and 476 previous arthroscopies, respectively, were needed. CONCLUSIONS: This study provides quantified guidance for arthroscopic training and highlights the positive relationship between arthroscopic case load and arthroscopic competency. We have estimated that the number of arthroscopies required to achieve competency in a basic arthroscopic task exceed those recommended in some countries. These estimates provide useful guidance to those responsible for training program. CLINICAL RELEVANCE: The numbers to achieve competent arthroscopic performance in the assessed simulated tasks exceed what is recommended and what is possible during surgical training programs in some countries

The influences of partial saturation on cone penetration tests in silty gold tailings

Laboratory-controlled cone penetration test results of a silty gold tailings in a variety of saturated and unsaturated states, obtained using two calibration chambers, are presented then interpreted using a state parameter-based approach. The research was conducted as part of the TAILLIQ project (tailliq.com), funded by the Australian Research Council and six mining companies, and involving four Australian universities.Cone penetration resistances, which increase due to the presence of suction when the tailings are unsaturated, can be normalised using the initial mean effective stress to establish a relationship with the initial state parameter. The relationship is applicable to saturated and unsaturated conditions, as long as the presence of suction hardening as well as the influence of suction on the mean effective stress are accounted for, and as long as the cone penetrations occur under pseudo drained conditions. The relationships enable state parameters and void ratios to be back-calculated from normalised cone penetration resistances

Structure/Function Analysis of Recurrent Mutations in SETD2 Protein Reveals a Critical and Conserved Role for a SET Domain Residue in Maintaining Protein Stability and Histone H3 Lys-36 Trimethylation

The yeast Set2 histone methyltransferase is a critical enzyme that plays a number of key roles in gene transcription and DNA repair. Recently, the human homologue, SETD2, was found to be recurrently mutated in a significant percentage of renal cell carcinomas, raising the possibility that the activity of SETD2 is tumor-suppressive. Using budding yeast and human cell line model systems, we examined the functional significance of two evolutionarily conserved residues in SETD2 that are recurrently mutated in human cancers. Whereas one of these mutations (R2510H), located in the Set2 Rpb1 interaction domain, did not result in an observable defect in SETD2 enzymatic function, a second mutation in the catalytic domain of this enzyme (R1625C) resulted in a complete loss of histone H3 Lys-36 trimethylation (H3K36me3). This mutant showed unchanged thermal stability as compared with the wild type protein but diminished binding to the histone H3 tail. Surprisingly, mutation of the conserved residue in Set2 (R195C) similarly resulted in a complete loss of H3K36me3 but did not affect dimethylated histone H3 Lys-36 (H3K36me2) or functions associated with H3K36me2 in yeast. Collectively, these data imply a critical role for Arg-1625 in maintaining the protein interaction with H3 and specific H3K36me3 function of this enzyme, which is conserved from yeast to humans. They also may provide a refined biochemical explanation for how H3K36me3 loss leads to genomic instability and cancer

Characterization of Zebrafish von Willebrand Factor Reveals Conservation of Domain Structure, Multimerization, and Intracellular Storage

von Willebrand disease (VWD) is the most common inherited human bleeding disorder and is caused by quantitative or qualitative defects in von Willebrand factor (VWF). VWF is a secreted glycoprotein that circulates as large multimers. While reduced VWF is associated with bleeding, elevations in overall level or multimer size are implicated in thrombosis. The zebrafish is a powerful genetic model in which the hemostatic system is well conserved with mammals. The ability of this organism to generate thousands of offspring and its optical transparency make it unique and complementary to mammalian models of hemostasis. Previously, partial clones of zebrafish vwf have been identified, and some functional conservation has been demonstrated. In this paper we clone the complete zebrafish vwf cDNA and show that there is conservation of domain structure. Recombinant zebrafish Vwf forms large multimers and pseudo-Weibel-Palade bodies (WPBs) in cell culture. Larval expression is in the pharyngeal arches, yolk sac, and intestinal epithelium. These results provide a foundation for continued study of zebrafish Vwf that may further our understanding of the mechanisms of VWD

Somatic genetic aberrations in benign breast disease and the risk of subsequent breast cancer

It is largely unknown how the development of breast cancer (BC) is transduced by somatic genetic alterations in the benign breast. Since benign breast disease is an established risk factor for BC, we established a case-control study of women with a history of benign breast biopsy (BBB). Cases developed BC at least one year after BBB and controls did not develop BC over an average of 17 years following BBB. 135 cases were matched to 69 controls by age and type of benign change: non-proliferative or proliferation without atypia (PDWA). Whole-exome sequencing (WES) was performed for the BBB. Germline DNA (available from n = 26 participants) was utilized to develop a mutation-calling pipeline, to allow differentiation of somatic from germline variants. Among the 204 subjects, two known mutational signatures were identified, along with a currently uncatalogued signature that was significantly associated with triple negative BC (TNBC) (p = 0.007). The uncatalogued mutational signature was validated in 109 TNBCs from TCGA (p = 0.001). Compared to non-proliferative samples, PDWA harbors more abundant mutations at PIK3CA pH1047R (p < 0.001). Among the 26 BBB whose somatic copy number variation could be assessed, deletion of MLH3 is significantly associated with the mismatch repair mutational signature (p < 0.001). Matched BBB-cancer pairs were available for ten cases; several mutations were shared between BBB and cancers. This initial study of WES of BBB shows its potential for the identification of genetic alterations that portend breast oncogenesis. In future larger studies, robust personalized breast cancer risk indicators leading to novel interception paradigms can be assessed

Mechanisms controlling anaemia in Trypanosoma congolense infected mice.

Trypanosoma congolense are extracellular protozoan parasites of the blood stream of artiodactyls and are one of the main constraints on cattle production in Africa. In cattle, anaemia is the key feature of disease and persists after parasitaemia has declined to low or undetectable levels, but treatment to clear the parasites usually resolves the anaemia. The progress of anaemia after Trypanosoma congolense infection was followed in three mouse strains. Anaemia developed rapidly in all three strains until the peak of the first wave of parasitaemia. This was followed by a second phase, characterized by slower progress to severe anaemia in C57BL/6, by slow recovery in surviving A/J and a rapid recovery in BALB/c. There was no association between parasitaemia and severity of anaemia. Furthermore, functional T lymphocytes are not required for the induction of anaemia, since suppression of T cell activity with Cyclosporin A had neither an effect on the course of infection nor on anaemia. Expression of genes involved in erythropoiesis and iron metabolism was followed in spleen, liver and kidney tissues in the three strains of mice using microarrays. There was no evidence for a response to erythropoietin, consistent with anaemia of chronic disease, which is erythropoietin insensitive. However, the expression of transcription factors and genes involved in erythropoiesis and haemolysis did correlate with the expression of the inflammatory cytokines Il6 and Ifng. The innate immune response appears to be the major contributor to the inflammation associated with anaemia since suppression of T cells with CsA had no observable effect. Several transcription factors regulating haematopoiesis, Tal1, Gata1, Zfpm1 and Klf1 were expressed at consistently lower levels in C57BL/6 mice suggesting that these mice have a lower haematopoietic capacity and therefore less ability to recover from haemolysis induced anaemia after infection