Glioma Chemotherapy Sensitization Mediated by Base Excision Repair Inhibition and its Potential Application

The incidence and mortality of brain tumors have not changed over the last 3 decades and pose a significant burden on the healthcare system of the United States. Temozolomide (TMZ) is the preferred chemotherapeutic agent for the treatment of brain tumors and base excision repair (BER) is a major mechanism for the repair of TMZ-induced DNA base lesions. BER inhibition, either by interrupting the delicate balance of the expression of key BER proteins or by chemical inhibitors, enhances cytotoxicity of chemotherapeutic DNA damaging agents such as TMZ. Understanding the mechanisms of enhanced cytotoxicity brought on by BER inhibition has great public health significance. By using DNA polymerase ß (Polß) deficiency as a model of BER inhibition, I report that DNA damage-induced cytotoxicity due to Polß deficiency triggers cell death dependent on PARP activation yet independent of poly(ADP-ribose) (PAR) or PAR-catabolite signaling. Cell death is rescued by the NAD+ metabolite NMN and is synergistic with inhibition of NAD+ biosynthesis demonstrating that DNA damage-induced cytotoxicity mediated via BER inhibition is primarily dependent on cellular metabolite bioavailability. I offer a mechanistic justification for the elevated alkylation-induced cytotoxicity of Polß deficient cells, suggesting a linkage between DNA repair, cell survival and cellular bioenergetics. Resistance to TMZ is partially attributed to efficient repair of TMZ-induced DNA lesions. Using the human glioma cell lines LN428 and T98G, I report here that potentiation of TMZ via BER inhibition (methoxyamine (MX), the PARP inhibitors PJ34 and ABT-888 or depletion (knockdown) of PARG) is greatly enhanced by increasing BER initiation via over-expression of MPG. I also show that MX-induced potentiation of TMZ in MPG expressing glioma cells is abrogated by elevated-expression of the rate-limiting BER enzyme Polß, suggesting that cells proficient for BER readily repair AP sites even in the presence of MX. This study demonstrates that increased initiation of BER via MPG over-expression, together with inhibition of repair following initiation, further sensitizes glioma cells to alkylating agent TMZ, suggesting that the expression level of MPG might be used to predict the effectiveness of BER inhibition-induced potentiation of TMZ in glioma cells

The Improvement of Motor Cooling Through Stator Profile Optimization using CFD Analysis in Hermetic Scroll Compressors

With the increased pressure of cost, hermetic compressor sizing become an important part of the design optimization process, while maintain the same performance level in the same time. Hermetic compressor motor design also face the same challenge. However, reducing motor size for same compressor capacity will increase the motor power density, with the same motor cooling design as before, motor running temperature will be increased and this affect both motor life and reliability as well as passing UL certification requirement for compressors using OLP ( internal overload protector). Hermetic motor cooling improvement using thermal modelling has been investigated before by using thermal network method, with limited accuracy since this do not taken all thermal correlation between motor and compressors. (refer to Purdue paper: thermal modelling ro the motor in semi-hermetic screw refrigeration compressor under part load conditions) However, the real situation in terms of thermal and fluid distribution which affect motor cooling inside the compressor in much more complicated than a pure thermal lumped circuit can represent. With the usage of fluid and thermal coupled simulation method today, we can simulate and understand more accurately the correlation between motor and compressor heat transfer and fluid distribution to optimize motor cooling channel, both in static and dynamic stage, and keep motor temperature under the accepted level while main a good flow for the overall compressor performance. In this paper, different geometry of stator outer diameter profiles are investigated, to balance between the motor efficiency impacts versus the motor temperature increase, compressor and conclude the optimization in terms of stator outer profile for the compressor structure discussed in this paper. Motor efficiency results are calculated and also tested, motor cooling optimization also calculated and tested inside compressor. From the research work done here, we can see that by using CFD tool (ANSYS), compressor motor design engineers can find the optimal stator lamination design, and understand the biggest influence factor to motor cooling, but not important for motor electromagnetic design and performance. In future, if the design concentrated on the important factors, and optimize the motor cooling, compressor design in terms of sizing and cooling correlation would be well balanced between cost and performance

Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility

Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578-1565) and controls (n = 337-1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts.c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.Peer reviewe

Function of TRP channels in monocytes/macrophages

The transient receptor potential channel (TRP channel) family is a kind of non- specific cation channel widely distributed in various tissues and organs of the human body, including the respiratory system, cardiovascular system, immune system, etc. It has been reported that various TRP channels are expressed in mammalian macrophages. TRP channels may be involved in various signaling pathways in the development of various systemic diseases through changes in intracellular concentrations of cations such as calcium and magnesium. These TRP channels may also intermingle with macrophage activation signals to jointly regulate the occurrence and development of diseases. Here, we summarize recent findings on the expression and function of TRP channels in macrophages and discuss their role as modulators of macrophage activation and function. As research on TRP channels in health and disease progresses, it is anticipated that positive or negative modulators of TRP channels for treating specific diseases may be promising therapeutic options for the prevention and/or treatment of disease

Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility

Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578–1565) and controls (n = 337–1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts. c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.</p

Sound Absorption of Hemp Fibers (Cannabis Sativa L.) Based Nonwoven Fabrics and Composites: A Review

Compared to the commonly used synthetic fibrous materials, natural fiber represents an eco-friendly solution in various engineering fields. Noise control is an important application of natural fibers due to the unique acoustic characteristics. Studies on the sound absorption of hemp fibers have attracted more and more attention in recent years. Generally, hemp products for sound absorption mainly including nonwoven fabrics and fiber-reinforced composites. This review has gathered the most recent advances on the acoustics of hemp fibers, and also the sound absorption design principles of hemp-based materials. A detailed information related to the improvement of the sound absorption properties of hemp is given, which mainly including the optimization of manufacturing, materials component, bulk density, morphologies, and structural parameters, etc. Hemp fibers exhibit robust acoustical performance, and the present work is beneficial to the development of sound absorption hemp-based materials

Discovering Significant Sequential Patterns in Data Stream by an Efficient Two-Phase Procedure

One essential topic of mining sequential patterns in the data stream is to optimize the time-space computations. However, more importantly, it should pay more attention to the significance of mining results as a large portion of them just response to the user-defined constraints purely by accident and they may have no statistical significance. In this paper, we propose FSSPDS, an efficient two-phase algorithm to discover the significant sequential patterns (SSPs) in the data stream with typical sliding windows, which has never been considered in existing problems. First, for generating SSPs candidates with high-quality, FSSPDS takes testable support and pattern length constraints into account and insignificant patterns were removed timely by a pattern-growth method. In the second phase, appropriate permutation testing is used to test the significance of the SSPs candidates. Exact permutation p values are obtained in a novel combination way based on unconditional Barnard’s test statistic which better reflects the process of data generations and collections. Experimental evaluations show that FSSPDS allows the discovery of SSPs in the data stream and rivals the state-of-the-art approaches efficiently under the control of family-wise error rate (FWER), especially for time efficiency, which was approximately an order of magnitude higher